Use of a NK-1 receptor antagonist and an antidepressant and/or an anti-anxiety agent

ABSTRACT

The present invention relates to the treatment or prevention of depression and/or anxiety by the administration of a combination of a specific class of NK-1 receptor antagonists and an antidepressant or anti-anxiety agent. The present invention also provides preclinical screens for anxiolytic and antidepressant activity of NK-1 receptor antagonists.

[0001] This invention relates to the treatment or prevention ofdepression and/or anxiety by the administration of a combination of aspecific class of NK-1 receptor antagonists and an antidepressant oranti-anxiety agent. The present invention also provides preclinicalscreens for anxiolytic and antidepressant activity of NK-1 receptorantagonists.

[0002] Major depression is characterised by feelings of intense sadnessand despair, mental slowing and loss of concentration, pessimisticworry, agitation, and self-deprecation. Physical changes also occur,especially in severe or “melancholic” depression. These include insomniaor hypersomnia, anorexia and weight loss (or sometimes overeating),decreased energy and libido, and disruption of normal circadian rhythmsof activity, body temperature, and many endocrine functions.

[0003] Treatment regimens commonly include the use of tricyclicantidepressants, monoamine oxidase inhibitors, some psychotropic drugs,lithium carbonate, and electroconvulsive therapy (ECT) (see R. J.Baldessarini in Goodman & Gilman's The Pharmacological Basis ofTherapeutics, 9th Edition, Chapter 19, McGraw-Hill, 1996 for a review).More recently, new classes of antidepressant drugs are being developedincluding selective serotonin reuptake inhibitors (SSRIs), specificmonoamine reuptake inhibitors and 5-HT_(1A) receptor agonists,antagonists and partial agonists.

[0004] Anxiety is an emotional condition characterised by feelings suchas apprehension and fear accompanied by physical sympoms such astachycardia, increased respiration, sweating and tremor. It is a normalemotion but when it is severe and disabling it becomes pathological.

[0005] Anxiety disorders are generally treated using benzodiazepinesedative-antianxiety agents. Potent benzodiazepines are effective inpanic disorder as well as in generalised anxiety disorder, however, therisks associated with drug dependency may limit their long-term use.5-HT_(1A) receptor partial agonists also have useful anxiolytic andother psychotropic activity, and less likelihood of sedation anddependance (see R. J. Baldessarini in Goodman & Gilman's ThePharmacological Basis of Therapeutics, 9th Edition, Chapter 18,McGraw-Hill, 1996 for a review).

[0006] Neurokinin 1 (NK-1; substance P) receptor antagonists are beingdeveloped for the treatment of a number of physiological disordersassociated with an excess or imbalance of tachykinins, and in particularsubstance P. Examples of such conditions include disorders of thecentral nervous system such as anxiety, depression and psychosis (see,for instance, International (PCT) patent specification Nos. WO 95/16679,WO 95/18124 and WO 95/23798).

[0007] It might therefore be desirable to investigate the treatment ofdepression and/or anxiety using a combination of a tachykinin antagonistand an antidepressant and/or an anti-anxiety agent. Indeed, such adesideratum has already been considered in International (PCT) patentspecification No. WO 96/24353 (published Aug. 15, 1996) which claimsmethods for the treatment of psychiatric disorders using a combinationof a tachykinin antagonist and a serotonin agonist or selectiveserotonin reuptake inhibitor. However, the disclosure of WO 96/24353does not provide any teaching as to whether the claimed combination hasany efficacy and in particular there is no direction towards specificcombinations which might potentiate the antidepressant or anxiolyticeffects of the individual therapeutic agents. There is no cleardirection from WO 96/24353 to which class of tachykinin antagonist (e.g.NK-1, NK-2 or NK-3 receptor antagonists) would be of use in the claimedcombinations, nor how a person of ordinary skill in the art mightidentify suitable compounds for use in combination with a serotoninagonist or a selective serotonin reuptake inhibitor. Furthermore, thereis no teaching which would enable a person of ordinary skill in the artto identify those compounds with sustained activity following oraladministration for use in the claimed combinations. At best, WO 96/24353merely recites in one document that which was already recognised in theart, namely that tachykinin antagonists might be of use in the treatmentof psychiatric disorders and that serotonin agonists and selectiveserotonin reuptake inhibitors are effective in the treatment ofpsychiatric disorders.

[0008] There therefore remains a need for an effective combination of anantidepressant and/or an anti-anxiety agent with a NK-1 receptorantagonist, which combination provides an unexpected and advantageousantidepressant or anxiolytic effect. Such combinations may for exampleprovide an enhanced antidepressant or anxiolytic effect. They may alsoprovide for a rapid onset of action to combat depression and/or anxietythereby enabling prescription on an “as-needed” basis.

[0009] CNS-penetrant NK-1 receptor antagonists have been found toprovide an unexpected effect relevant to the treatment and prevention ofdepression and/or anxiety when used in combination with anantidepressant or anti-anxiety agent. While not being bound to anyparticular theory of operation, an enhanced effect at treating orpreventing a psychological stress response in an animal assay isobserved with the combination of drugs than would be expected fromeither drug alone In particular, combination therapy of a CNS-penetrantNK-1 receptor antagonist selected from the compounds of formulae (I),(II), (III), (IV) and (V), and a selective serotonin reuptake inhibitoror a 5-HT_(1A) receptor agonist or antagonist effectively inhibitsseparation-induced vocalisations in guinea-pig pups. This is indicativeof efficacy in the treatment of depression and/or anxiety. Suchunexpected results would not have been predicted based on thedisclosures in the art.

[0010] The present invention accordingly provides the use of aCNS-penetrant NK-1 receptor antagonist and an antidepressant oranti-anxiety agent for the manufacture of a medicament for the treatmentor prevention of depression and/or anxiety.

[0011] The present invention also provides a method for the treatment orprevention of depression and/or anxiety, which method comprisesadministration to a patient in need of such treatment an amount of aCNS-penetrant NK-1 receptor antagonist and an amount of anantidepressant or anti-anxiety agent, such that together they giveeffective relief.

[0012] In a further aspect of the present invention, there is provided apharmaceutical composition comprising a CNS-penetrant NK-1 receptorantagonist and an antidepressant or anti-anxiety agent, together with atleast one pharmaceutically acceptable carrier or excipient.

[0013] It will be appreciated that the CNS-penetrant NK-1 receptorantagonist and antidepressant or anti-anxiety agent may be present as acombined preparation for simultaneous, separate or sequential use forthe treatment or prevention of depression and/or anxiety. Such combinedpreparations may be, for example, in the form of a twin pack.

[0014] In a further or alternative aspect of the present invention,there is therefore provided a product comprising a CNS-penetrant NK-1receptor antagonist and an antidepressant or anti-anxiety agent as acombined preparation for simultaneous, separate or sequential use in thetreatment or prevention of depression and/or anxiety.

[0015] It will be appreciated that when using a combination of thepresent invention, both the CNS-penetrant NK-1 receptor antagonist andthe antidepressant or anti-anxiety agent will be administered to apatient, within a reasonable period of time. The compounds may be in thesame pharmaceutically acceptable carrier and therefore administeredsimultaneously. They may be in separate pharmaceutical carriers such asconventional oral dosage forms which are taken simultaneously. The term“combination” also refers to the case where the compounds are providedin separate dosage forms and are administered sequentially. Therefore,by way of example, the antidepressant or anti-anxiety agent may beadministered as a tablet and then, within a reasonable period of time,the CNS-penetrant NK-1 receptor antagonist may be administered either asan oral dosage form such as a tablet or a fast-dissolving oral dosageform. By a “fast dissolving oral formulation” is meant, an oral deliveryform which when placed on the tongue of a patient, dissolves withinabout 10 seconds.

[0016] By “reasonable period of time” is meant a time period that is notin excess of about 1 hour. That is, for example, if the antidepressantor anti-anxiety agent is provided as a tablet, then within one hour, theCNS-penetrant NK-1 receptor antagonist should be administered, either inthe same type of dosage form, or another dosage form which provideseffective delivery of the medicament.

[0017] The compositions of the present invention are useful for thetreatment of depression. As used herein, the term “depression” includesdepressive disorders, for example, single episodic or recurrent majordepressive disorders, and dysthymic disorders, depressive neurosis, andneurotic depression; melancholic depression including anorexia, weightloss, insomnia and early morning waking, and psychomotor retardation;atypical depression (or reactive depression) including increasedappetite, hypersomnia, psychomotor agitation or irritability, anxietyand phobias; seasonal affective disorder; or bipolar disorders or manicdepression, for example, bipolar I disorder, bipolar II disorder andcyclothymic disorder.

[0018] Other mood disorders encompassed within the term “depression”include dysthymic disorder with early or late onset and with or withoutatypical features; dementia of the Alzheimer's type, with early or lateonset, with depressed mood; vascular dementia with depressed mood; mooddisorders induced by alcohol, amphetamines, cocaine, hallucinogens,inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics andother substances; schizoaffective disorder of the depressed type; andadjustment disorder with depressed mood.

[0019] The compositions of the present invention are useful for thetreatment of anxiety. As used herein, the term “anxiety” includesanxiety disorders, such as panic disorder with or without agoraphobia,agoraphobia without history of panic disorder, specific phobias, forexample, specific animal phobias, social phobias, obsessive-compulsivedisorder, stress disorders including post-traumatic stress disorder andacute stress disorder, and generalised anxiety disorders.

[0020] “Generalised anxiety” is typically defined as an extended period(e.g. at least six months) of excessive anxiety or worry with symptomson most days of that period. The anxiety and worry is difficult tocontrol and may be accompanied by restlessness, being easily fatigued,difficulty concentrating, irritability, muscle tension, and disturbedsleep.

[0021] “Panic disorder” is defined as the presence of recurrent panicattacks followed by at least one month of persistent concern abouthaving another panic attack. A “panic attack” is a discrete period inwhich there is a sudden onset of intense apprehension, fearfulness orterror. During a panic attack, the individual may experience a varietyof symptoms including palpitations, sweating, trembling, shortness ofbreath, chest pain, nausea and dizziness. Panic disorder may occur withor without agoraphobia.

[0022] “Phobias” includes agoraphobia, specific phobias and socialphobias. “Agoraphobia” is characterised by an anxiety about being inplaces or situations from which escape might be difficult orembarrassing or in which help may not be available in the event of apanic attack. Agoraphobia may occur without history of a panic attack. A“specific phobia” is characterised by clinically significant anxietyprovoked by exposure to a specific feared object or situation. Specificphobias include the following subtypes: animal type, cued by animals orinsects; natural environment type, cued by objects in the naturalenvironment, for example storms, heights or water;blood-injection-injury type, cued by the sight of blood or an injury orby seeing or receiving an injection or other invasive medical procedure;situational type, cued by a specific situation such as publictransportation, tunnels, bridges, elevators, flying, driving or enclosedspaces; and other type where fear is cued by other stimuli. Specificphobias may also be referred to as simple phobias. A “social phobia” ischaracterised by clinically significant anxiety provoked by exposure tocertain types of social or performance circumstances. Social phobia mayalso be referred to as social anxiety disorder.

[0023] Other anxiety disorders encompassed within the term “anxiety”include anxiety disorders induced by alcohol, amphetamines, caffeine,cannabis, cocaine, hallucinogens, inhalants, phencyclidine, sedatives,hypnotics, anxiolytics and other substances, and adjustment disorderswith anxiety or with mixed anxiety and depression.

[0024] Anxiety may be present with or without other disorders such asdepression in mixed anxiety and depressive disorders. The compositionsof the present invention are therefore useful in the treatment ofanxiety with or without accompanying depression.

[0025] The compositions of the present invention are especially usefulfor the treatment of or prevention of depression and/or anxiety wherethe use of an antidepressant or anti-anxiety agent is generallyprescribed. By the use of a combination of a CNS-penetrant NK-1 receptorantagonist and an antidepressant or anti-anxiety agent in accordancewith the present invention, it is now also possible to treat or preventdepression and/or anxiety in patients for whom conventionalantidepressant or anti-anxiety therapy might not be wholly successful orwhere dependance upon the antidepressant or anti-anxiety therapy isprevalent.

[0026] Suitable classes of antidepressant agent of use in the presentinvention include norepinephrine reuptake inhibitors, selectiveserotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors(MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotoninand noradrenaline reuptake inhibitors (SNRIs), corticotropin releasingfactor (CRF) antagonists, α-adrenoreceptor antagonists and atypicalantidepressants.

[0027] Another class of antidepressant agent of use in the presentinvention are noradrenergic and specific serotonergic antidepressants(NaSSAs). A suitable example of a NaSSA is mirtazapine.

[0028] Suitable norepinephrine reuptake inhibitors of use in the presentinvention include tertiary amine tricyclics and secondary aminetricyclics. Suitable examples of tertiary amine tricyclics include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine, andpharmaceutically acceptable salts thereof. Suitable examples ofsecondary amine tricyclics include: amoxapine, desipramine, maprotiline,nortriptyline and protriptyline, and pharmaceutically acceptable saltsthereof.

[0029] Another norepinephrine reuptake inhibitor of use in the presentinvention is reboxetine.

[0030] Suitable selective serotonin reuptake inhibitors of use in thepresent invention include: fluoxetine, fluvoxamine, paroxetine andsertraline, and pharmaceutically acceptable salts thereof.

[0031] Suitable monoamine oxidase inhibitors of use in the presentinvention include: isocarboxazid, phenelzine, tranylcypromine andselegiline, and pharmaceutically acceptable salts thereof.

[0032] Suitable reversible inhibitors of monoamine oxidase of use in thepresent invention include: moclobemide, and pharmaceutically acceptablesalts thereof.

[0033] Suitable serotonin and noradrenaline reuptake inhibitors of usein the present invention include: venlafaxine, and pharmaceuticallyacceptable salts thereof.

[0034] Suitable CRF antagonists of use in the present invention includethose compounds described in International Patent Specification Nos. WO94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.

[0035] Suitable atypical antidepressants of use in the present inventioninclude: bupropion, lithium, nefazodone, trazodone and viloxazine, andpharmaceutically acceptable salts thereof. Another suitable atypicalantidepressant is sibutramine.

[0036] Other antidepressants of use in the present invention includeadinazolam, alaproclate, amineptine, amitriptyline/chlordiazepoxidecombination, atipamezole, azamianserin, bazinaprine, befuraline,bifemelane, binodaline, bipenamol, brofaromine bupropion, caroxazone,cericlamine, cianopramine, cimoxatone, citalopram, clemeprol,clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin,droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine,fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole,levoprotiline, litoxetine, lofepramine, medifoxamine, metapramine,metralindole, mianserin, milnacipran, minaprine, mirtazapine,montirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine,orotirelin, oxaflozane, pinazepam, pirlindone, pizotyline, ritanserin,rolipram, sercloremine, setiptiline, sibutramine, sulbutiamine,sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine,tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride,viqualine, zimelidine and zometapine, and pharmaceutically acceptablesalts thereof, and St. John's wort herb, or Hypericum perforatum, orextracts thereof.

[0037] Suitable classes of anti-anxiety agent of use in the presentinvention include benzodiazepines and 5-HT_(1A) agonists or antagonists,especially 5-HT_(1A) partial agonists, and corticotropin releasingfactor (CRF) antagonists. In addition to benzodiazepines, other suitableclasses of anti-anxiety agent are nonbenzodiazepine sedative-hypnoticdrugs such as zolpidem; mood-stabilizing drugs such as clobazam,gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stiripentol andvigabatrin; and barbiturates.

[0038] Suitable benzodiazepines of use in the present invention include:alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam,halazepam, lorazepam, oxazepam and prazepam, and pharmaceuticallyacceptable salts thereof.

[0039] Suitable 5-HT_(1A) receptor agonists or antagonists of use in thepresent invention include, in particular, the 5-HT_(1A) receptor partialagonists buspirone, flesinoxan, gepirone and ipsapirone, andpharmaceutically acceptable salts thereof. An example of a compound with5-HT_(1A) receptor antagonist/partial agonist activity is pindolol.

[0040] Suitable CRF antagonists of use in the present invention includethose compounds described in International Patent Specification Nos. WO94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.

[0041] Another class of anti-anxiety agent of use in the presentinvention are compounds having muscarinic cholinergic activity. Suitablecompounds in this class include ml muscarinic cholinergic receptoragonists such as those compounds described in European PatentSpecification Nos. 0 709 093, 0 709 094 and 0 773 021, and Internationalpatent Specification No. WO 96/12711.

[0042] Another class of anti-anxiety agent of use in the presentinvention are compounds acting on ion channels. Suitable compounds inthis class include carbamazepine, lamotrigine and valproate, andpharmaceutically acceptable salts thereof.

[0043] Particularly preferred CNS-penetrant NK-1 receptor antagonistsare those described in European Patent Specification No. 0 577 394, i.e.compounds of formula (I):

[0044] or a pharmaceutically acceptable salt thereof, wherein:

[0045] R¹ is selected from the group consisting of:

[0046] (1) hydrogen;

[0047] (2) C₁₋₆alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0048] (a) hydroxy,

[0049] (b) oxo,

[0050] (c) C₁₋₆alkoxy,

[0051] (d) phenyl-C₁₋₃alkoxy,

[0052] (e) phenyl,

[0053] (I) —CN,

[0054] (g) halo,

[0055] (h) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently selected from:

[0056] (i) hydrogen,

[0057] (ii) C₁₋₆alkyl,

[0058] (iii) hydroxy-C₁₋₆alkyl, and

[0059] (iv) phenyl,

[0060] (i) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0061] (j) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0062] (k) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0063] (l) —COR⁹, wherein R⁹ is as defined above,

[0064] (m) —CO₂R⁹, wherein R⁹ is as defined above,

[0065] (n) heterocycle, wherein the heterocycle is selected from thegroup consisting of:

[0066] (A) benzimidazolyl,

[0067] (B) benzofuranyl,

[0068] (C) benzthiophenyl,

[0069] (D) benzoxazolyl,

[0070] (E) furanyl,

[0071] (F) imidazolyl,

[0072] (G) indolyl,

[0073] (H) isoxazolyl,

[0074] (I) isothiazolyl,

[0075] (J) isothiazolyl,

[0076] (J) oxadiazolyl,

[0077] (K) oxazolyl,

[0078] (L) pyrazinyl,

[0079] (M) pyrazolyl,

[0080] (N) pyridyl,

[0081] (O) pyrimidyl,

[0082] (P) pyrrolyl,

[0083] (Q) quinolyl,

[0084] (R) tetrazolyl,

[0085] (S) thiadiazolyl,

[0086] (T) thiazolyl,

[0087] (U) thienyl,

[0088] (V) triazolyl,

[0089] (W) azetidinyl,

[0090] (X) 1,4-dioxanyl,

[0091] (Y) hexahydroazepinyl,

[0092] (Z) oxanyl,

[0093] (AA) piperazinyl,

[0094] (AB) piperidinyl,

[0095] (AC) pyrrolidinyl,

[0096] (AD) tetrahydrofuranyl, and

[0097] (AE) tetrahydrothienyl,

[0098] and wherein the heterocylcle is unsubstituted or substituted withone or more substituent(s) selected from:

[0099] (i) C₁₋₆alkyl, unsubstituted or substituted with halo, —CF₃,—OCH₃, or phenyl,

[0100] (ii) C₁₋₆alkoxy,

[0101] (iii) oxo,

[0102] (iv) hydroxy,

[0103] (v) thioxo,

[0104] (vi) —SR⁹, wherein R⁹ is as defined above,

[0105] (vii) halo,

[0106] (viii) cyano,

[0107] (ix) phenyl,

[0108] (x) trifluoromethyl,

[0109] (xi) —(CH₂)_(m)—NR⁹R¹⁰, wherein m is 0, 1 or 2, and R⁹ and R¹⁰are as defined above,

[0110] (xii) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0111] (xiii) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0112] (xiv) —CO₂R⁹, wherein R⁹ is as defined above, and

[0113] (xv) —(CH2)_(m)—OR⁹, wherein m and R⁹ are as defined above;

[0114] (3) C₂₋₆alkenyl, unsubstituted or substituted with one or more ofthe substituent(s) selected from:

[0115] (a) hydroxy,

[0116] (b) oxo,

[0117] (c) C₁₋₆alkoxy,

[0118] (d) phenyl-C₁₋₃alkoxy,

[0119] (e) phenyl,

[0120] (f) —CN,

[0121] (g) halo,

[0122] (h) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0123] (i) —COR⁹, wherein R⁹ is as defined above,

[0124] (j) —CO₂R⁹, wherein R⁹ is as defined above,

[0125] (k) heterocycle, wherein the heterocycle is as defined above;

[0126] (4) C₂₋₆alkynyl;

[0127] (5) phenyl, unsubstitued or substituted with one or more of thesubstituent(s) selected from:

[0128] (a) hydroxy,

[0129] (b) C₁₋₆alkoxy,

[0130] (c) C₁₋₆alkyl,

[0131] (d) C₂₋₅alkenyl,

[0132] (e) halo,

[0133] (f) —CN,

[0134] (g) —NO₂,

[0135] (h) —CF₃,

[0136] (i) —(CH2)_(m)—NR⁹R¹⁰, wherein m, R⁹ and R¹⁰ are as definedabove,

[0137] (j) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0138] (k) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0139] (l) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0140] (m) —CO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0141] (n) —COR⁹, wherein R⁹ is as defined above,

[0142] (o) —CO₂R⁹, wherein R⁹ is as defined above;

[0143] R² and R³ are independently selected from the group consistingof:

[0144] (1) hydrogen;

[0145] (2) C₁₋₆alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0146] (a) hydroxy,

[0147] (b) oxo,

[0148] (c) C₁₋₆alkoxy,

[0149] (d) phenyl-C₁₋₃alkoxy,

[0150] (e) phenyl,

[0151] (f) —CN,

[0152] (g) halo,

[0153] (h) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently selected from:

[0154] (i) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0155] (j) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0156] (k) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0157] (l) —COR⁹, wherein R⁹ is as defined above, and

[0158] (m) —CO₂R⁹, wherein R⁹ is as defined above;

[0159] (3) C₂₋₆alkenyl, unsubstituted or substituted with one or more ofthe substituent(s) selected from:

[0160] (a) hydroxy,

[0161] (b) oxo,

[0162] (c) C₁₋₆alkoxy,

[0163] (d) phenyl-C₁₋₃alkoxy,

[0164] (e) phenyl,

[0165] (f) —CN,

[0166] (g) halo,

[0167] (h) —CONR⁹R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

[0168] (i) —COR⁹, wherein R⁹ is as defined above,

[0169] (j) —CO₂R⁹, wherein R⁹ is as defined above;

[0170] (4) C₂₋₆alkynyl;

[0171] (5) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0172] (a) hydroxy,

[0173] (b) C₁₋₆alkoxy,

[0174] (c) C₁₋₆alkyl,

[0175] (d) C₂₋₅alkenyl,

[0176] (e) halo,

[0177] (f) —CN,

[0178] (g) —NO₂,

[0179] (h) —CF₃,

[0180] (i) —(CH2)_(m)—NR⁹R¹⁰, wherein m, R⁹ and R¹⁰ are as definedabove,

[0181] (j) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0182] (k) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0183] (l) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0184] (m) —CO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0185] (n) —COR⁹, wherein R⁹ is as defined above,

[0186] (o) —CO₂R⁹, wherein R⁹ is as defined above; and the groups R¹ andR² may be joined together to form a heterocyclic ring selected from thegroup consisting of:

[0187] (a) pyrrolidinyl,

[0188] (b) piperidinyl,

[0189] (c) pyrrolyl,

[0190] (d) pyridinyl,

[0191] (e) imidazolyl,

[0192] (f) oxazolyl, and

[0193] (g) thiazolyl, and wherein the heterocyclic ring is unsubstitutedor substituted with one or more substituent(s) selected from:

[0194] (i) C₁₋₆alkyl,

[0195] (ii) oxo,

[0196] (iii) C₁₋₆alkoxy,

[0197] (iv) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0198] (v) halo, and

[0199] (vi) trifluoromethyl; and the groups R² and R³ may be joinedtogether to form a carbocyclic ring selected from the group consistingof:

[0200] (a) cyclopentyl,

[0201] (b) cyclohexyl,

[0202] (c) phenyl, and wherein the carbocyclic ring is unsubstituted orsubstituted with one or more substituents selected from:

[0203] (i) C₁₋₆alkyl,

[0204] (ii) C 16alkoxy,

[0205] (iii) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0206] (iv) halo, and

[0207] (v) trifluoromethyl; and the groups R² and R³ may be joinedtogether to form a heterocyclic ring selected from the group consistingof:

[0208] (a) pyrrolidinyl,

[0209] (b) piperidinyl,

[0210] (c) pyrrolyl,

[0211] (d) pyridinyl,

[0212] (e) imidazolyl,

[0213] (f) furanyl,

[0214] (g) oxazolyl,

[0215] (h) thienyl, and

[0216] (i) thiazolyl, and wherein the heterocyclic ring is unsubstitutedor substituted with one or more substituent(s) selected from:

[0217] (i) C₁₋₆alkyl,

[0218] (ii) oxo,

[0219] (iii) C₁₋₆alkoxy,

[0220] (iv) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0221] (v) halo, and

[0222] (vi) trifluoromethyl;

[0223] X is selected from the group consisting of:

[0224] (1) —O—,

[0225] (2) —S—,

[0226] (3) —SO—, and

[0227] (4) —SO₂—;

[0228] R⁴ is selected from the group consisting of:

[0229] (1)

[0230] (2) —Y—C₁₋₈alkyl, wherein alkyl is unsubstituted or substitutedwith one or more of the substituents selected from:

[0231] (a) hydroxy,

[0232] (b) oxo,

[0233] (c) C₁₋₆alkoxy,

[0234] (d) phenyl-C₁₋₃alkoxy,

[0235] (e) phenyl,

[0236] (f) —CN,

[0237] (g) halo,

[0238] (h) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0239] (i) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0240] (j) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0241] (k) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0242] (l) —COR⁹, wherein R⁹ is as defined above,

[0243] (m) —CO₂R⁹, wherein R⁹ is as defined above;

[0244] (3) —Y—C₂₋₆alkenyl, wherein the alkenyl is unsubstituted orsubstituted with one or more of the substituent(s) selected from:

[0245] (a) hydroxy,

[0246] (b) oxo,

[0247] (c) C₁₋₆alkoxy,

[0248] (d) phenyl-C₁₋₃alkoxy,

[0249] (e) phenyl,

[0250] (f) —CN,

[0251] (g) halo,

[0252] (h) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0253] (i) —COR⁹, wherein R⁹ is as defined above,

[0254] (j) —CO₂R⁹, wherein R⁹ is as defined above,

[0255] (4) —O(CO)-phenyl, wherein the phenyl is unsubstituted orsubstituted with one or more of R⁶, R⁷and R⁸;

[0256] R⁵ is selected from the group consisting of:

[0257] (1) phenyl, unsubstituted or substituted with one or more of R¹¹,R¹² and R¹³;

[0258] (2) C₁₋₈alkyl, unsubstituted or substituted with one or more ofthe substituent(s) selected from:

[0259] (a) hydroxy,

[0260] (b) oxo,

[0261] (c) C₁₋₆alkoxy,

[0262] (d) phenyl-C₁₋₃alkoxy,

[0263] (e) phenyl,

[0264] (f) —CN,

[0265] (g) halo,

[0266] (h) NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0267] (i) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0268] (j) NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0269] (k) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0270] (l) —COR⁹, wherein R⁹ is as defined above,

[0271] (m) —CO₂R⁹, wherein R⁹ is as defined above;

[0272] (3) C₂₋₆alkenyl, unsubstituted or substituted with one or more ofthe substituent(s) selected from:

[0273] (a) hydroxy,

[0274] (b) oxo,

[0275] (c) C₁₋₆alkoxy,

[0276] (d) phenyl-C₁₋₃alkoxy,

[0277] (e) phenyl,

[0278] (f) —CN,

[0279] (g) halo,

[0280] (h) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0281] (i) —COR⁹, wherein R⁹ is as defined above,

[0282] (j) —CO₂R⁹, wherein R⁹ is as defined above;

[0283] (4) heterocycle, wherein the heterocycle is as defined above;

[0284] R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of:

[0285] (1) hydrogen;

[0286] (2) C₁₋₆alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0287] (a) hydroxy,

[0288] (b) oxo,

[0289] (c) C₁₋₆alkoxy,

[0290] (d) phenyl-C₁₋₃alkoxy,

[0291] (e) phenyl,

[0292] (f) —CN,

[0293] (g) halo,

[0294] (h) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0295] (i) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0296] (j) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0297] (k) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0298] (l) —COR⁹, wherein R⁹ is as defined above, and

[0299] (m) —CO₂R⁹, wherein R⁹ is as defined above;

[0300] (3) C₂₋₆alkenyl, unsubstituted or substituted with one or more ofthe substituent(s) selected from:

[0301] (a) hydroxy,

[0302] (b) oxo,

[0303] (c) C₁₋₆alkoxy,

[0304] (d) phenyl-C₁₋₃alkoxy,

[0305] (e) phenyl,

[0306] (f) —CN,

[0307] (g) halo,

[0308] (h) —CONR⁹R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

[0309] (i) —COR⁹ wherein R⁹ is as defined above,

[0310] (j) —CO₂R⁹, wherein R⁹ is as defined above;

[0311] (4) C₂₋₆alkynyl;

[0312] (5) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0313] (a) hydroxy,

[0314] (b) C₁₋₆alkoxy,

[0315] (c) C₁₋₆alkyl,

[0316] (d) C₂₋₅alkenyl,

[0317] (e) halo,

[0318] (f) —CN,

[0319] (g) —NO₂,

[0320] (h) —CF₃,

[0321] (i) —(CH2)_(m)—NR⁹R¹⁰, wherein m, R⁹ and R¹⁰ are as definedabove,

[0322] (j) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0323] (k) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0324] (l) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0325] (m) —CO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0326] (n) —COR⁹, wherein R⁹ is as defined above;

[0327] (o) —CO₂R⁹, wherein R⁹ is as defined above;

[0328] (6) halo,

[0329] (7) —CN,

[0330] (8) —CF₃,

[0331] (9) —NO₂,

[0332] (10) —SR^(14,) wherein R¹⁴ is hydrogen or C₁₋₅alkyl,

[0333] (11) —SOR^(14,) wherein R¹⁴ is as defined above,

[0334] (12) —SO₂R¹⁴, wherein R¹⁴ is as defined above,

[0335] (13) NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0336] (14) CONR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0337] (15) NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0338] (16) NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0339] (17) hydroxy,

[0340] (18) C₁₋₆alkoxy,

[0341] (19) COR⁹, wherein R⁹ is as defined above,

[0342] (20) CO₂R⁹, wherein R⁹ is as defined above,

[0343] R¹¹, R¹² and R¹³ are independently selected from the definitionsof R^(6,) R⁷ and R⁸, or —OX;

[0344] Y is selected from the group consisting of:

[0345] (1) a single bond,

[0346] (2) —O—,

[0347] (3) —S—,

[0348] (4) —CO—,

[0349] (5) —CH₂—,

[0350] (6) —CHR¹⁵, and

[0351] (7) —CR¹⁵R¹⁶—, wherein R¹⁵ and R¹⁶ are independently selectedfrom the group consisting of:

[0352] (a) C₁₋₆alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0353] (i) hydroxy,

[0354] (ii) oxo,

[0355] (iii) C₁₋₆alkoxy,

[0356] (iv) phenyl-C₁₋₃alkoxy,

[0357] (v) phenyl,

[0358] (vi) —CN,

[0359] (vii) halo,

[0360] (viii) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0361] (ix) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0362] (x) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0363] (xi) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0364] (xii) —COR⁹, wherein R⁹ is as defined above, and

[0365] (xiii) —CO₂R⁹, wherein R⁹ is as defined above;

[0366] (b) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0367] (i) hydroxy,

[0368] (ii) C₁₋₆alkoxy,

[0369] (iii) C₁₋₆alkyl,

[0370] (iv) C₂₋₅alkenyl,

[0371] (v) halo,

[0372] (vi) —CN,

[0373] (vii) —NO₂,

[0374] (viii) —CF₃,

[0375] (ix) —(CH2)_(m)—NR⁹R¹⁰, wherein m, R⁹ and R¹⁰ are as definedabove,

[0376] (x) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0377] (xi) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0378] (xii) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0379] (xiii) —CO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0380] (xiv) —COR⁹, wherein R⁹ is as defined above, and

[0381] (xv) —CO₂R⁹, wherein R⁹ is as defined above;

[0382] Z is selected from:

[0383] (1) hydrogen,

[0384] (2) C₁₋₄alkyl, and

[0385] (3) hydroxy, with the proviso that if Y is —O—, Z is other thanhydroxy, or if Y is —CHR¹⁵—, then Z and R¹⁵ may be joined together toform a double bond.

[0386] Particularly preferred compounds of formula (I) are thosewherein: R¹ is selected from the group consisting of:

[0387] (1) C₁₋₆alkyl, substituted with one or more of the substituentsselected from:

[0388] (a) heterocycle, wherein the heterocycle is selected from thegroup consisting of:

[0389] (A) benzimidazolyl,

[0390] (B) imidazolyl,

[0391] (C) isoxazolyl,

[0392] (D) isothiazolyl,

[0393] (E) oxadiazolyl,

[0394] (F) pyrazinyl,

[0395] (G) pyrazolyl,

[0396] (H) pyridyl,

[0397] (I) pyrrolyl,

[0398] (J) tetrazolyl,

[0399] (K) thiadiazolyl,

[0400] (L) triazolyl, and

[0401] (M) piperidinyl, and wherein the heterocycle is unsubstituted orsubstituted with one or more substituent(s) selected from:

[0402] (i) C₁₋₆alkyl, unsubstituted or substituted with halo, —CF₃,—OCH₃, or phenyl,

[0403] (ii) C₁₋₆alkoxy,

[0404] (iii) oxo,

[0405] (iv) thioxo,

[0406] (v) cyano,

[0407] (vi) —SCH₃,

[0408] (vii) phenyl,

[0409] (viii) hydroxy,

[0410] (ix) trifluoromethyl,

[0411] (x) —(CH2)_(m)—NR⁹R¹⁰, wherein m is 0, 1 or 2, and R⁹ and R¹⁰ areindependently selected from:

[0412] (I) hydrogen,

[0413] (II) C₁₋₆alkyl,

[0414] (III) hydroxyC₁₋₆alkyl, and

[0415] (IV) phenyl,

[0416] (xi) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above, and

[0417] (xii) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0418] R² and R³ are independently selected from the group consistingof:

[0419] (1) hydrogen;

[0420] (2) C₁₋₆alkyl

[0421] (3) C₂₋₆alkenyl, and

[0422] (5) phenyl;

[0423] X is —O—;

[0424] R⁴ is

[0425] R⁵ is phenyl, unsubstituted or substituted with halo;

[0426] R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of:

[0427] (1) hydrogen,

[0428] (2) C₁₋₆alkyl,

[0429] (3) halo, and

[0430] (4) —CF₃;

[0431] Y is —O—; and

[0432] Z is hydrogen or C₁₋₄alkyl;

[0433] and pharmaceutically acceptable salts thereof.

[0434] A particularly preferred compound of formula (I) is2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)pheny)lethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;or a pharmaceutically acceptable salt thereof.

[0435] Further preferred CNS-penetrant NK-1 receptor antagonists arethose described in International (PCT) Patent Specification No. WO95/18124, i.e. compounds of formula (II):

[0436] or a pharmaceutically acceptable salt or prodrug thereof, wherein

[0437] R¹ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, CF₃, NO₂, CN,SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy, where R^(a) andR^(b) each independently represent hydrogen or C₁₋₄alkyl;

[0438] R² is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy substituted byC₁₋₄alkoxy or CF₃;

[0439] R³ is hydrogen, halogen or CF₃;

[0440] R⁴ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, CF₃, NO₂, CN,SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy, where R^(a) andR^(b) each independently represent hydrogen or C₁₋₄alkyl;

[0441] R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy substituted byC₁₋₄alkoxy or CF₃;

[0442] R⁶ is a 5-membered or 6-membered heterocyclic ring containing 2or 3 nitrogen atoms optionally substituted by ═O, ═S or a C₁₋₄alkylgroup, and optionally substituted by a group of the formula ZNR⁷R⁸ where

[0443] Z is C₁₋₆alkylene or C₃₋₆cycloalkylene;

[0444] R⁷ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl orC₃₋₇cycloalkylC₁₋₄alkyl, or C₂₋₄alkyl substituted by C₁₋₄alkoxy orhydroxyl;

[0445] R⁸ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl orC₃₋₇cycloalkylC₁₋₄alkyl, or C₂₋₄alkyl substituted by one or twosubstituents selected from C₁₋₄alkoxy, hydroxyl or a 4, 5 or 6 memberedheteroaliphatic ring containing one or two heteroatoms selected from N,O and S;

[0446] or R⁷, R⁸ and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by ahydroxy group, and optionally containing a double bond, which ring mayoptionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)₂or a second nitrogen atom which will be part of a NH or NR^(c) moietywhere R^(c) is C₁₋₄alkyl optionally substituted by hydroxy orC₁₋₄alkoxy;

[0447] or R⁷, R⁸ and the nitrogen atom to which they are attached form anon-aromatic azabicyclic ring system of 6 to 12 ring atoms;

[0448] or Z, R⁷ and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms which may optionally containan oxygen ring atom;

[0449] R^(9a) and R^(9b) are each independently hydrogen or C₁₋₄alkyl,or R^(9a) and R^(9b) are joined so, together with the carbon atoms towhich they are attached, there is formed a C₅₋₇ ring;

[0450] X is an alkylene chain of 1 to 4 carbon atoms optionallysubstituted by oxo; and

[0451] Y is a C₁₋₄alkyl group optionally substituted by a hydroxylgroup;

[0452] with the proviso that if Y is C₁₋₄alkyl, R⁶ is susbstituted atleast by a group of formula ZNR⁷R⁸ as defined above.

[0453] Particularly preferred compounds of formula (II) are those offormula (IIa) and pharmaceutically acceptable salts thereof:

[0454] wherein:

[0455] A¹ is fluorine or CF₃;

[0456] A² is fluorine or CF₃;

[0457] A³ is fluorine or hydrogen;

[0458] and X, Y and R⁶ are as defined in relation to formula (II).

[0459] Particularly preferred compounds of formula (II) include:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;and pharmaceutically acceptable salts thereof

[0460] Further preferred CNS-penetrant NK-1 receptor antagonists arethose described in European Patent Specification No. WO 95/23798, i.e.compounds of formula (III):

[0461] or a pharmaceutically acceptable salt thereof, wherein:

[0462] R² and R³ are independently selected from the group consistingof:

[0463] (1) hydrogen,

[0464] (2) C₁₋₆alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0465] (a) hydroxy,

[0466] (b) oxo,

[0467] (c) C₁₋₆alkoxy,

[0468] (d) phenyl-C₁₋₃alkoxy,

[0469] (e) phenyl,

[0470] (f) —CN,

[0471] (g) halo,

[0472] (h) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently selected from:

[0473] (I) hydrogen,

[0474] (ii) C₁₋₆alkyl,

[0475] (iii) hydroxy-C₁₋₆alkyl, and

[0476] (iv) phenyl,

[0477] (i) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0478] (j) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0479] (k) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0480] (l) —COR⁹, wherein R⁹ is as defined above, and

[0481] (m) —CO₂R⁹, wherein R⁹ is as defined above;

[0482] (3) C₂₋₆alkenyl, unsubstituted or substituted with one or more ofthe substituent(s) selected from:

[0483] (a) hydroxy,

[0484] (b) oxo,

[0485] (c) C₁₋₆alkoxy,

[0486] (d) phenyl-C₁₋₃alkoxy,

[0487] (e) phenyl,

[0488] (f) —CN,

[0489] (g) halo,

[0490] (h) —CONR⁹R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

[0491] (i) —COR⁹ wherein R⁹ is as defined above,

[0492] (j) —CO₂R⁹, wherein R⁹ is as defined above;

[0493] (4) C₂₋₆alkynyl;

[0494] (5) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0495] (a) hydroxy,

[0496] (b) C₁₋₆alkoxy,

[0497] (c) C₁₋₆alkyl,

[0498] (d) C₂₋₅alkenyl,

[0499] (e) halo,

[0500] (f) —CN,

[0501] (g) —NO₂,

[0502] (h) —CF₃,

[0503] (i) —(CH₂)_(m)—NR⁹R¹⁰, wherein m, R⁹ and R¹⁰ are as definedabove,

[0504] (j) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0505] (k) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0506] (l) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0507] (m) —CO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0508] (n) —COR⁹, wherein R⁹ is as defined above,

[0509] (o) —CO₂R⁹, wherein R⁹ is as defined above; and the groups R² andR³ may be joined together to form a carbocyclic ring selected from thegroup consisting of:

[0510] (a) cyclopentyl,

[0511] (b) cyclohexyl,

[0512] (c) phenyl, and wherein the carbocyclic ring is unsubstituted orsubstituted with one or more substituents selected from:

[0513] (i) C₁₋₆alkyl,

[0514] (ii) C₁₋₆alkoxy,

[0515] (iii) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0516] (iv) halo, and

[0517] (v) trifluoromethyl; and the groups R² and R³ may be joinedtogether to form a heterocyclic ring selected from the group consistingof:

[0518] (a) pyrrolidinyl,

[0519] (b) piperidinyl,

[0520] (c) pyrrolyl,

[0521] (d) pyridinyl,

[0522] (e) imidazolyl,

[0523] (f) furanyl,

[0524] (g) oxazolyl,

[0525] (h) thienyl, and

[0526] (i) thiazolyl, and wherein the heterocyclic ring is unsubstitutedor substituted with one or more substituent(s) selected from:

[0527] (i) C₁₋₆alkyl,

[0528] (ii) oxo,

[0529] (iii) C₁₋₆alkoxy,

[0530] (iv) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0531] (v) halo, and

[0532] (vi) trifluoromethyl;

[0533] R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of:

[0534] (1) hydrogen;

[0535] (2) C₁₋₆alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0536] (a) hydroxy,

[0537] (b) oxo,

[0538] (c) C₁₋₆alkoxy,

[0539] (d) phenyl-C₁₋₃alkoxy,

[0540] (e) phenyl,

[0541] (D —CN,

[0542] (g) halo,

[0543] (h) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0544] (i) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0545] (j) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0546] (k) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0547] (l) —COR⁹, wherein R⁹ is as defined above, and

[0548] (m) —CO₂R⁹, wherein R⁹ is as defined above;

[0549] (3) C₂₋₆alkenyl, unsubstituted or substituted with one or more ofthe substituent(s) selected from:

[0550] (a) hydroxy,

[0551] (b) oxo,

[0552] (c) C₁₋₆alkoxy,

[0553] (d) phenyl-C₁₋₃alkoxy,

[0554] (e) phenyl,

[0555] (f) —CN,

[0556] (g) halo,

[0557] (h) —CONR⁹R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

[0558] (i) —COR⁹ wherein R⁹ is as defined above,

[0559] (j) —CO₂R⁹, wherein R⁹ is as defined above;

[0560] (4) C₂₋₆alkynyl;

[0561] (5) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0562] (a) hydroxy,

[0563] (b) C₁₋₆alkoxy,

[0564] (c) C₁₋₆alkyl,

[0565] (d) C₂₋₅alkenyl,

[0566] (e) halo,

[0567] (f) —CN,

[0568] (g) —NO₂,

[0569] (h) —CF₃,

[0570] (i) —(CH2)_(m)—NR⁹R¹⁰, wherein m, R⁹ and R¹⁰ are as definedabove,

[0571] (j) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0572] (k) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0573] (l) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0574] (m) —CO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0575] (n) —COR⁹, wherein R⁹ is as defined above,

[0576] (o) —CO₂R⁹, wherein R⁹ is as defined above;

[0577] (6) halo,

[0578] (7) —CN,

[0579] (8) —CF₃,

[0580] (9) —NO₂,

[0581] (10) —SR¹⁴, wherein R¹⁴ is hydrogen or C₁₋₅alkyl,

[0582] (11) —SOR¹⁴, wherein R¹⁴ is as defined above,

[0583] (12) —SO₂R¹⁴, wherein R¹⁴ is as defined above,

[0584] (13) NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0585] (14) CONR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0586] (15) NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0587] (16) NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0588] (17) hydroxy,

[0589] (18) C₁₋₆alkoxy,

[0590] (19) COR⁹, wherein R⁹ is as defined above,

[0591] (20) CO₂R⁹, wherein R⁹ is as defined above,

[0592] (21) 2-pyridyl,

[0593] (22) 3-pyridyl,

[0594] (23) 4-pyridyl,

[0595] (24) 5-tetrazolyl,

[0596] (25) 2-oxazolyl, and

[0597] (26) 2-thiazolyl;

[0598] R¹¹, R¹² and R¹³ are independently selected from the definitionsof R⁶, R⁷ and R⁸, or —OX;

[0599] A is selected from the group consisting of:

[0600] (1) C₁₋₆alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0601] (a) hydroxy,

[0602] (b) oxo,

[0603] (c) C₁₋₆alkoxy,

[0604] (d) phenyl-C₁₋₃alkoxy,

[0605] (e) phenyl,

[0606] (f) —CN,

[0607] (g) halo, wherein halo is fluoro, chloro, bromo or iodo,

[0608] (h) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0609] (i) —NR⁹COR¹ ⁰, wherein R⁹ and R¹⁰ are as defined above,

[0610] (j) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0611] (k) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0612] (l) —COR⁹, wherein R⁹ is as defined above, and

[0613] (m) —CO₂R⁹, wherein R⁹ is as defined above;

[0614] (2) C₂₋₆alkenyl, unsubstituted or substituted with one or more ofthe substituent(s) selected from:

[0615] (a) hydroxy,

[0616] (b) oxo,

[0617] (c) C₁₋₆alkoxy,

[0618] (d) phenyl-C₁₋₃alkoxy,

[0619] (e) phenyl,

[0620] (f) —CN,

[0621] (g) halo,

[0622] (h) —CONR⁹R¹⁰ wherein R⁹ and R¹⁰ are as defined above,

[0623] (i) —COR⁹ wherein R⁹ is as defined above, and

[0624] (j) —CO₂R⁹, wherein R⁹ is as defined above; and

[0625] (3) C₂₋₆alkynyl;

[0626] B is a heterocycle, wherein the heterocycle is selected from thegroup consisting of:

[0627]  and wherein the heterocycle may be substituted in addition to —Xwith one or more substituent(s) selected from:

[0628] (i) C₁₋₆alkyl, unsubstituted or substituted with halo, —CF₃,—OCH₃, or phenyl,

[0629] (ii) C₁₋₆alkoxy,

[0630] (iii) oxo,

[0631] (iv) hydroxy,

[0632] (v) thioxo,

[0633] (vi) —SR⁹, wherein R⁹ is as defined above,

[0634] (vii) halo,

[0635] (viii) cyano,

[0636] (ix) phenyl,

[0637] (x) trifluoromethyl,

[0638] (xi) —(CH₂)_(m)—NR⁹R¹⁰, wherein m is 0, 1 or 2, and R⁹ and R¹⁰are as defined above,

[0639] (xii) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0640] (xiii) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0641] (xiv) —CO₂R⁹, wherein R⁹ is as defined above, and

[0642] (xv) —(CH2)_(m)—OR⁹, wherein m and R⁹ are as defined above;

[0643] p is 0 or 1;

[0644] X is selected from:

[0645] (a) —PO(OH)O⁻.M⁺, wherein M⁺ is a pharmaceutically acceptablemonovalent counterion,

[0646] (b) —PO(O⁻)₂.2M⁺,

[0647] (c) —PO(O⁻)₂.D²⁺, wherein D²⁺ is a pharmaceutically acceptabledivalent counterion,

[0648] (d) —CH(R⁴)—PO(OH)O⁻.M⁺, wherein R⁴ is hydrogen or C₁₋₃alkyl,

[0649] (e) —CH(R⁴)—PO(O⁻)₂.2M⁺,

[0650] (f) —CH(R⁴)—PO(O⁻)₂.D²⁺,

[0651] (g) —SO₃ ⁻.M⁺,

[0652] (h) —CH(R⁴)—SO₃ ⁻.M⁺,

[0653] (i) —CO—CH₂CH₂—CO₂ ⁻.M⁺,

[0654] (j) —CH(CH₃)—O—CO—R⁵, wherein R⁵ is selected from the groupconsisting of:

[0655] (k) hydrogen, with the proviso that if p is 0 and none of R¹¹,R¹² or R¹³ are —OX, then X is other than hydrogen;

[0656] Y is selected from the group consisting of:

[0657] (1) a single bond,

[0658] (2) —O—,

[0659] (3) —S—,

[0660] (4) —CO—,

[0661] (5) —CH₂—,

[0662] (6) —CHR¹⁵—, and

[0663] (7) —CR¹⁵R¹⁶—, wherein R¹⁵ and R¹⁶ are independently selectedfrom the group consisting of:

[0664] (a) C₁₋₆alkyl, unsubstituted or substituted with one or more ofthe substituents selected from:

[0665] (i) hydroxy,

[0666] (ii) oxo,

[0667] (iii) C₁₋₆alkoxy,

[0668] (iv) phenyl-C₁₋₃alkoxy,

[0669] (v) phenyl,

[0670] (vi) —CN,

[0671] (vii) halo,

[0672] (viii) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0673] (ix) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0674] (x) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0675] (xi) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0676] (xii) —COR⁹, wherein R⁹ is as defined above, and

[0677] (xiii) —CO₂R⁹, wherein R⁹ is as defined above;

[0678] (b) phenyl, unsubstituted or substituted with one or more of thesubstituent(s) selected from:

[0679] (i) hydroxy,

[0680] (ii) C₁₋₆alkoxy,

[0681] (iii) C₁₋₆alkyl,

[0682] (iv) C₂₋₅alkenyl,

[0683] (v) halo,

[0684] (vi) —CN,

[0685] (vii) —NO₂,

[0686] (viii) —CF₃,

[0687] (ix) —(CH2)_(m)—NR⁹R¹⁰, wherein m, R⁹ and R¹⁰ are as definedabove,

[0688] (x) —NR⁹COR¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0689] (xi) —NR⁹CO₂R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0690] (xii) —CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0691] (xiii) —CO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above,

[0692] (xiv) —COR⁹, wherein R⁹ is as defined above, and

[0693] (xv) —CO₂R⁹, wherein R⁹ is as defined above;

[0694] Z is selected from:

[0695] (1) hydrogen,

[0696] (2) C₁₋₆alkyl, and

[0697] (3) hydroxy, with the proviso that if Y is —O—, Z is other thanhydroxy, or if Y is —CHR¹⁵—, then Z and R¹⁵ may be joined together toform a double bond.

[0698] Particularly preferred compounds of formula (III) are thosewherein: R² and R³ are independently selected from the group consistingof:

[0699] (1) hydrogen,

[0700] (2) C₁₋₆alkyl,

[0701] (3) C₂₋₆alkenyl, and

[0702] (4) phenyl;

[0703] R⁶, R⁷ and R⁸ are independently selected from the groupconsisting of:

[0704] (1) hydrogen,

[0705] (2) C₁₋₆alkyl,

[0706] (3) fluoro,

[0707] (4) chloro,

[0708] (5) bromo,

[0709] (6) iodo, and

[0710] (7) —CF₃;

[0711] R¹¹, R¹² and R¹³ are independently selected from the groupconsisting of:

[0712] (1) fluoro,

[0713] (2) chloro,

[0714] (3) bromo, and

[0715] (4) iodo;

[0716] A is unsubstituted ₁₋₆alkyl;

[0717] B is selected from the group consisting of:

[0718] p is 0 or 1;

[0719] X is selected from:

[0720] (a) —PO(OH)O⁻.M⁺, wherein M⁺ is a pharmaceutically acceptablemonovalent counterion,

[0721] (b) —PO(O⁻)₂.2M⁺,

[0722] (c) —PO(O⁻)₂.D²⁺, wherein D²⁺ is a pharmaceutically acceptabledivalent counterion,

[0723] (d) —CH(R⁴)—PO(OH)O⁻.M⁺, wherein R⁴ is hydrogen or C₁₋₃alkyl,

[0724] (e) —CH(R⁴)—PO(O⁻)₂.2M⁺,

[0725] (f) —CH(R⁴)—PO(O⁻)₂.D²⁺,

[0726] (i) —CO—CH₂CH₂—CO₂ ⁻.M⁺,

[0727] (j) —CH(CH₃)—O—CO—R⁵, wherein R⁵ is selected from the groupconsisting of:

[0728] Y is —O—;

[0729] Z is hydrogen or C₁₋₆alkyl;

[0730] and pharmaceutically acceptable salts thereof.

[0731] Particularly preferred compounds of formula (III) include:

[0732] (1)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholineN-oxide;

[0733] (2)2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4-(ethoxycarbonyloxy-1-ethyl)-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;

[0734] (3)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;

[0735] (4)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;

[0736] (5)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-triazolo)methyl)morpholine;

[0737] (6)2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-triazolo)methyl)morpholine;

[0738] (7)2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;

[0739] and pharmaceutically acceptable salts thereof.

[0740] Further preferred CNS-penetrant NK-1 receptor antagonists arethose described in European Patent Specification No. WO 96/05181, i.e.compounds of formula (IV):

[0741] wherein

[0742] X is a group of the formula NR⁶R⁷ or a C- or N-linked imidazolylring;

[0743] Y is hydrogen or C₁₋₄alkyl optionally substituted by a hydroxygroup;

[0744] R¹ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, CF₃, NO₂, CN,SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy, wherein R^(a) andR^(b) each independently represent hydrogen or C₁₋₄alkyl;

[0745] R² is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy substituted byC₁₋₄alkoxy or CF₃;

[0746] R³ is hydrogen, halogen or CF₃;

[0747] R⁴ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, CF₃,NO₂, CN, SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a), CONR^(a)R^(b),C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₄alkyl substituted by C₁₋₄alkoxy, whereinR^(a) and R^(b) are as previously defined;

[0748] R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy substituted byC₁₋₄alkoxy or CF₃;

[0749] R⁶ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, phenyl, or C₂₋₄alkyl substituted by C₁₋₄alkoxyor hydroxy;

[0750] R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, phenyl, or C₂₋₄alkyl substituted by one or twosubstituents selected from C₁₋₄alkoxy, hydroxy or a 4, 5 or 6 memberedheteroaliphatic ring containing one or two heteroatoms selected from N,O and S;

[0751] or R⁶ and R⁷, together with the nitrogen atom to which they areattached, form a saturated or partially saturated heterocyclic ring of 4to 7 ring atoms, which ring may optionally contain in the ring oneoxygen or sulphur atom or a group selected from NR⁸, S(O) or S(O)2 andwhich ring may be optionally substituted by one or two groups selectedfrom hydroxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, oxo, COR^(a) or CO₂R^(a)where R^(a) is as previously defined;

[0752] or R⁶ and R⁷ together with the nitrogen atom to which they areattached, form a non-aromatic azabicyclic ring system of 6 to 12 ringatoms;

[0753] R⁸ is hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl orC₁₋₄alkoxyC₁₋₄alkyl; and

[0754] R^(9a) and R^(9b) are each independently hydrogen or C₁₋₄alkyl,or R^(9a) and R^(9b) are joined so, together with the carbon atoms towhich they are attached, there is formed a C₅₋₇ ring; andpharmaceutically acceptable salts thereof.

[0755] Particularly preferred compounds of formula (IV) are those offormula (IVa) and pharmaceutically acceptable salts thereof:

[0756] wherein

[0757] A¹ is fluorine or CF₃;

[0758] A² is fluorine or CF₃;

[0759] A³ is fluorine or hydrogen; and X and Y are as defined inrelation to formula (I).

[0760] Specific compounds of formula (IV) of use in the presentinvention include:

[0761]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)morpholine;

[0762] 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;

[0763] b4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

[0764]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-imidazolylbut-2-yn-yl)morpholine;

[0765]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(N-methylpiperazinyl)but-2-yn-yl)morpholine;

[0766]4-(4-bis(2-methoxyethyl)aminobut-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

[0767]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-pyrrolidinobut-2-yn-yl)morpholine;

[0768]3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-morpholinobut-2-yn-yl)morpholine;

[0769]3-(S)-(4-fluorophenyl)-4-(4-morpholinobut-2-yn-yl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;

[0770]4-(4-azetidinylbut-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;

[0771]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-(2-methoxyethyl)-N-methyl)aminobut-2-yn-yl)-3-(S)-phenylmorpholine;

[0772]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-cyclopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;

[0773]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-(N-isopropyl-N-(2-methoxyethyl)amino)but-2-yn-yl)-3-(S)-phenylmorpholine;

[0774] 4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl-2-hydroxyethoxy)morpholine;

[0775]4-(4-azetidinylbut-2yn-yl)-3-(S)-(4-fluorophenyl)-2-(R)-(1-(S)-(3-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxyethoxy)morpholine;

[0776]2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(4-(N,N-dimethylamino)but-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;

[0777]4-(4-azetidinylbut-2-yn-yl)-2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)morpholine;

[0778]4-(4-N-bis(2-methoxy)ethyl-N-methylamino)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

[0779]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)morpholine;

[0780]4-(4-(7-azabicyclo[2.2.1]heptano)but-2-yn-yl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

[0781]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-diisopropylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;

[0782]2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(4-(2-(S)-(methoxymethyl)pyrrolidino)but-2-yn-yl)-3-(S)-phenylmorpholine;

[0783]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-(2-(S)-(hydroxymethyl)pyrrolidino)but-2-yn-yl)morpholine;and pharmaceutically acceptable salts thereof.

[0784] Further preferred CNS-penetrant NK-1 receptor antagonists arethose described in European Patent Specification No. WO 96/07649, i.e.compounds of formula (V):

[0785] wherein

[0786] R¹ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, CF₃, NO₂, CN,CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₄alkylsubstituted by C₁₋₄alkoxy, and wherein R^(a) and R^(b) are eachindependently hydrogen or C₁₋₄alkyl;

[0787] R² is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy substituted byC₁₋₄alkoxy or CF₃;

[0788] R³ is hydrogen, halogen or CF₃;

[0789] R⁴ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, CF₃,NO₂, CN, CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₄alkylsubstituted by C₁₋₄alkoxy, wherein R^(a) and R^(b) are as previouslydefined;

[0790] R⁵ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy substituted byC₁₋₄alkoxy or CF₃;

[0791] R⁶ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, phenyl, or C₂₋₄alkyl substituted by C₁₋₄alkoxyor hydroxy;

[0792] R⁷ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, phenyl, C₂₋₄alkyl substituted by C₁₋₄alkoxy orhydroxy, or the group C(═NR^(c))NR^(a)R^(b), where R^(a) and R^(b) areas previously defined and R^(c) is hydrogen, C₁₋₆alkyl, CN or COR^(a);

[0793] or R⁶ and R⁷, together with the nitrogen atom to which they areattached, form a saturated heterocyclic ring of 4 to 7 ring atoms whichmay optionally contain in the ring one oxygen or sulphur atom or a groupselected from NR⁸, S(O) or S(O)₂ and which ring may be optionallysubstituted by one or two groups selected from phenyl, benzyl,hydroxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxy, oxo, COR^(a) or CO₂R^(a)where R^(a) is as previously defined;

[0794] or R⁶ and R⁷, together with the nitrogen atom to which they areattached, form a piperidino ring substituted by a spiro-fused indene orindoline group, each of which may be unsubstituted or substituted on anyavailable carbon atom by a group selected from C₁₋₆alkyl, C₁₋₆alkoxy,hydroxy, halogen, cyano, trifluoromethyl, SO₂C₁₋₆alkyl, NR^(a)R^(b),NR^(a)COR^(b) or CONR^(a)R^(b); or, in the case of an indoline group, onthe nitrogen atom by a group selected from C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, phenylC₁₋₄alkyl, CO₂R^(a), CONR^(a)R^(b),SOR^(a) or SO₂R^(a), where R^(a) and R^(b) are as previously defined;

[0795] R⁸ is hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl orC₁₋₄alkoxyC₁₋₄alkyl;

[0796] R^(9a) and R^(9b) are each independently hydrogen or C₁₋₄alkyl,or R^(9a) and R^(9b) are joined so, together with the carbon atoms towhich they are attached, there is formed a C₅₋₇ ring;

[0797] X is selected from —CH₂CH₂—, —COCH₂— or —CH₂CO—; and

[0798] Y is hydrogen, or C₁₋₄alkyl optionally substituted by a hydroxylgroup;

[0799] or a pharmaceutically acceptable salt thereof.

[0800] Particularly preferred compounds of formula (V) are those offormula (Va) and pharmaceutically acceptable salts thereof:

[0801] wherein

[0802] A¹ is hydrogen, fluorine or CF₃;

[0803] A² is fluorine or CF₃;

[0804] A³ is fluorine or hydrogen; and X, Y, R⁶ and R⁷ are as defined inrelation to formula (V).

[0805] Specific compounds of formula (V) of use in the present inventioninclude:

[0806]4-(2-aminoethyl)-2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine;

[0807]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2-pyrrolidinoethyl)morpholine;

[0808]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2-morpholinoethyl)morpholine;

[0809]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2-(2′-(S)-carboxypyrrolidino)ethyl)-3-(S)-(4-fluorophenyl)morpholine;

[0810]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(2-(2′-(R)-hydroxymethylpyrrolidino)ethyl)morpholine;

[0811]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2-(4′-carbomethoxy-2′-oxopyrrolidino)ethyl)-3-(S)-(4-fluorophenyl)morpholine;

[0812]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(2-(N′-carboethoxy)-guanidino)ethyl)-3-(S)-(4-fluorophenyl)morpholine;

[0813]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(2-(4-phenylpiperidino)ethyl)morpholine;

[0814]3-(S)-phenyl-4-(2-(4-phenylpiperidino)ethyl)-2-(R)-(1-(R)-(3-(trifluoromethyl)phenyl)ethoxy)morpholine;

[0815]2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(2-(spiro(indene-3′,4-piperidino))ethyl)morpholine;

[0816]2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(2-(4-phenylpiperidino)ethyl)morpholine;

[0817]2-(R)-(1-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-4-(2-(1′-methylsulfonyl-spiro(indoline-3′,4-piperidino))ethyl)-3-(S)-phenylmorpholine;

[0818]2-(R)-(l-(R)-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl-4-(2-(4-piperidino)ethyl)morpholine;

[0819]2-(S)-(3,5-bis(trifluoromethyl)phenyl)methyloxy)-3-(S)-phenyl-4-(2-(4-phenylpiperidino)ethyl)morpholine;

[0820]4-(2-(4-benzylpiperidino)ethyl)-2-(S)-(3,5-bis(trifluoromethyl)phenyl)-methyloxy)-3-(S)-phenylmorpholine;

[0821] and pharmaceutically acceptable salts thereof.

[0822] The preferred compounds of formulae (I), (II), (III), (IV) and(V) will have the 2- and 3-substituents on the morpholine ring in thecis arrangement, the preferred stereochemistry being as shown in thefollowing general formula:

[0823] Where the benzyloxy moiety is (x-substituted, the preferredstereochemistry of the cc-carbon is either (R) when the substituent isan alkyl (e.g. methyl) group or (S) when the substituent is ahydroxyalkyl (e.g. hydroxymethyl) group.

[0824] Unless otherwise defined herein, suitable alkyl groups includestraight-chained and branched alkyl groups containing from 1 to 6 carbonatoms. Typical examples include methyl and ethyl groups, andstraight-chained or branched propyl and butyl groups. Particular alkylgroups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl andtert-butyl.

[0825] Unless otherwise defined herein, suitable alkenyl groups includestraight-chained and branched alkenyl groups containing from 2 to 6carbon atoms. Typical examples include vinyl and allyl groups.

[0826] Unless otherwise defined herein, suitable alkynyl groups includestraight-chained and branched alkynyl groups containing from 2 to 6carbon atoms. Typical examples include ethynyl and propargyl groups.

[0827] Unless otherwise defined herein, suitable cycloalkyl groupsinclude groups containing from 3 to 7 carbon atoms. Particularcycloalkyl groups are cyclopropyl and cyclohexyl.

[0828] Unless otherwise defined herein, suitable aryl groups includephenyl and naphthyl groups.

[0829] A particular aryl-C₁₋₆alkyl, e.g. phenyl-C₁₋₆alkyl, group isbenzyl.

[0830] Unless otherwise defined herein, suitable heteroaryl groupsinclude pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl,oxadiazolyl and thiadiazolyl groups.

[0831] The term “halogen” as used herein includes fluorine, chlorine,bromine and iodine.

[0832] The compounds of use in this invention may have one or moreasymmetric centres and can therefore exist as enantiomers and possiblyas diastereoisomers. It is to be understood that the present inventionrelates to the use of all such isomers and mixtures thereof.

[0833] Suitable pharmaceutically acceptable salts of the CNS-penetrantNK-1 receptor antagonists of use in the present invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound with a solution of a pharmaceutically acceptable non-toxicacid such as hydrochloric acid, fumaric acid, maleic acid, succinicacid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoricacid or sulphuric acid. Salts of amine groups may also comprise thequaternary ammonium salts in which the amino nitrogen atom carries analkyl, alkenyl, alkynyl or aralkyl group. Where the compound carries anacidic group, for example a carboxylic acid group, the present inventionalso contemplates salts thereof, preferably non-toxic pharmaceuticallyacceptable salts thereof, such as the sodium, potassium and calciumsalts thereof.

[0834] Suitable pharmaceutically acceptable salts of the antidepressantor anti-anxiety agent of use in the present invention include thosesalts described above in relation to the salts of CNS-penetrant NK-1receptor antagonists.

[0835] The present invention accordingly provides the use of aCNS-penetrant NK-1 receptor antagonist selected from the compounds offormulae (I), (II), (III), (IV) and (V) and an antidepressant oranti-anxiety agent for the manufacture of a medicament for the treatmentor prevention of depression and/or anxiety.

[0836] The present invention also provides a method for the treatment orprevention of depression and/or anxiety, which method comprisesadministration to a patient in need of such treatment an amount of aCNS-penetrant NK-1 receptor antagonist selected from the compounds offormulae (I), (II), (III), (IV) and (V) and an amount of anantidepressant or anti-anxiety agent such that together they giveeffective relief.

[0837] In a further aspect of the present invention, there is provided apharmaceutical composition comprising a CNS-penetrant NK-1 receptorantagonist selected from the compounds of formulae (I), (II), (III),(IV) and (V) and an antidepressant or anti-anxiety agent together withat least one pharmaceutically acceptable carrier or excipient.

[0838] It will be appreciated that the CNS-penetrant NK-1 receptorantagonist selected from the compounds of formulae (I), (II), (III),(IV) and (V) and and an antidepressant or anti-anxiety agent may bepresent as a combined preparation for simultaneous, separate orsequential use for the treatment or prevention of depression and/oranxiety. Such combined preparations may be, for example, in the form ofa twin pack.

[0839] In a further or alternative aspect of the present invention,there is therefore provided a product comprising a CNS-penetrant NK-1receptor antagonist selected from the compounds of formulae (I), (II),(III), (IV) and (V) and and an antidepressant or anti-anxiety agent as acombined preparation for simultaneous, separate or sequential use in thetreatment or prevention of depression and/or anxiety.

[0840] In a preferred aspect, the present invention accordingly providesthe use of a CNS-penetrant NK-1 receptor antagonist selected from thecompounds of formulae (I), (II), (III), (IV) and (V) and anantidepressant agent selected from the group consisting of:norepinephrine reuptake inhibitors, selective serotonin reuptakeinhibitors, monoamine oxidase inhibitors, reversible monoamine oxidaseinhibitors, serotonin and noradrenaline reuptake inhibitors,corticotropin releasing factor (CRF) antagonists, α-adrenoreceptorantagonists and atypical antidepressants, for the manufacture of amedicament for the treatment or prevention of depression and/or anxiety.

[0841] The present invention also provides a method for the treatment orprevention of depression and/or anxiety, which method comprisesadministration to a patient in need of such treatment an amount of aCNS-penetrant NK-1 receptor antagonist selected from the compounds offormulae (I), (II), (III), (IV) and (V) and an antidepressant agentselected from the group consisting of: norepinephrine reuptakeinhibitors, selective serotonin reuptake inhibitors, monoamine oxidaseinhibitors, reversible monoamine oxidase inhibitors, serotonin andnoradrenaline reuptake inhibitors, corticotropin releasing factor (CRF)antagonists, α-adrenoreceptor antagonists and atypical antidepressants,such that together they give effective relief.

[0842] In a further aspect of the present invention, there is provided apharmaceutical composition comprising a CNS-penetrant NK-1 receptorantagonist selected from the compounds of formulae (I), (II), (III),(IV) and (V) and an antidepressant agent selected from the groupconsisting of: norepinephrine reuptake inhibitors, selective serotoninreuptake inhibitors, monoamine oxidase inhibitors, reversible monoamineoxidase inhibitors, serotonin and noradrenaline reuptake inhibitors,corticotropin releasing factor (CRF) antagonists, α-adrenoreceptorantagonists and atypical antidepressants, together with at least onepharmaceutically acceptable carrier or excipient.

[0843] In a further or alternative aspect of the present invention,there is provided a product comprising a CNS-penetrant NK-1 receptorantagonist selected from the compounds of formulae (I), (II), (III),(IV) and (V) and an antidepressant agent selected from the groupconsisting of: norepinephrine reuptake inhibitors, selective serotoninreuptake inhibitors, monoamine oxidase inhibitors, reversible monoamineoxidase inhibitors, serotonin and noradrenaline reuptake inhibitors,corticotropin releasing factor (CRF) antagonists, α-adrenoreceptorantagonists and atypical antidepressants, as a combined preparation forsimultaneous, separate or sequential use in the treatment or preventionof depression and/or anxiety.

[0844] A particularly preferred class of antidepressant agent is theselective serotonin reuptake inhibitors, thus in a further preferredaspect, the present invention accordingly provides the use of aCNS-penetrant NK-1 receptor antagonist selected from the compounds offormulae (I), (II), (III), (IV) and (V) and a selective serotoninreuptake inhibitor for the manufacture of a medicament for the treatmentor prevention of depression and/or anxiety.

[0845] The present invention also provides a method for the treatment orprevention of depression and/or anxiety, which method comprisesadministration to a patient in need of such treatment an amount of aCNS-penetrant NK-1 receptor antagonist selected from the compounds offormulae (I), (II), (III), (IV) and (V) and an amount of a selectiveserotonin reuptake inhibitor, such that together they give effectiverelief.

[0846] In a further aspect of the present invention, there is provided apharmaceutical composition comprising a CNS-penetrant NK-1 receptorantagonist selected from the compounds of formulae (I), (II), (III),(IV) and (V) and a selective serotonin reuptake inhibitor, together withat least one pharmaceutically acceptable carrier or excipient.

[0847] In a further or alternative aspect of the present invention,there is provided a product comprising a CNS-penetrant NK-1 receptorantagonist selected from the compounds of formulae (I), (II), (III),(IV) and (V) and a selective serotonin reuptake inhibitor as a combinedpreparation for simultaneous, separate or sequential use in thetreatment or prevention of depression and/or anxiety.

[0848] A particularly preferred class of anti-anxiety agent is the5-HT_(1A) agonists or antagonists, especially the 5-HT_(1A) partialagonists, thus in a further preferred aspect, the present inventionaccordingly provides the use of a CNS-penetrant NK-1 receptor antagonistselected from the compounds of formulae (I), (II), (III), (IV) and (V)and a 5-HT_(1A) receptor agonist or antagonist for the manufacture of amedicament for the treatment or prevention of depression and/or anxiety.

[0849] The present invention also provides a method for the treatment orprevention of depression and/or anxiety, which method comprisesadministration to a patient in need of such treatment an amount of aCNS-penetrant NK-1 receptor antagonist selected from the compounds offormulae (I), (II), (III), (IV) and (V) and an amount of a 5-HT_(1A)receptor agonist or antagonist, such that together they give effectiverelief.

[0850] In a further aspect of the present invention, there is provided apharmaceutical composition comprising a CNS-penetrant NK-1 receptorantagonist selected from the compounds of formulae (I), (II), (III),(IV) and (V) and a 5-HT_(1A) receptor agonist or antagonist, togetherwith at least one pharmaceutically acceptable carrier or excipient.

[0851] In a further or alternative aspect of the present invention,there is provided a product comprising a CNS-penetrant NK-1 receptorantagonist selected from the compounds of formulae (I), (II), (III),(IV) and (V) and a 5-HT_(1A) receptor agonist or antagonist as acombined preparation for simultaneous, separate or sequential use in thetreatment or prevention of depression and/or anxiety.

[0852] As stated above, the CNS-penetrant NK-1 receptor antagonist andthe antidepressant or anti-anxiety agent may be formulated in a singlepharmaceutical composition or alternatively in individual pharmaceuticalcompositions for simultaneous, separate or sequential use in accordancewith the present invention.

[0853] It will be appreciated that it may be desirable to combine theCNS-penetrant NK-1 receptor antagonist with more than one antidepressantand/or anti-antiety agent. Thus “triple combination” or “multiplecombination” therapy is envisaged within the scope of the presentinvention, for example, use of a CNS-penetrant NK-1 receptor antagonistof formulae (1), (II), (III), (IV) or (V) in combination with aselective serotonin reuptake inhibitor, such as fluoxetine, and acompound with 5-HT_(1A) antagonist activity, such as pindolol.

[0854] Preferably the compositions according to the present inventionare in unit dosage forms such as tablets, pills, capsules, wafers andthe like. Additionally, the active ingredients may be presented asgranules or powders for extemporaneous formulation as volume definedsolutions or suspensions. Alternatively, the active ingredients may bepresented in ready-prepared volume defined solutions or suspensions.Preferred forms are tablets and capsules.

[0855] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g. water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

[0856] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally include aqueoussolutions, suitably flavoured syrups, aqueous or oil suspensions, andflavoured emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil, peanut oil or soybean oil, as well as elixirs and similarpharmaceutical vehicles. Suitable dispersing or suspending agents foraqueous suspensions include synthetic and natural gums such astragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0857] Compositions of the present invention may also be administeredvia the buccal cavity using conventional technology, for example,absorption wafers.

[0858] Compositions in the form of tablets, pills, capsules or wafersfor oral administration are particularly preferred.

[0859] The present invention further provides a process for thepreparation of a pharmaceutical composition comprising a CNS-penetrantNK-1 receptor antagonist and an antidepressant or anti-anxiety agent,which process comprises bringing a CNS-penetrant NK-1 receptorantagonist and an antidepressant or anti-anxiety agent, into associationwith a pharmaceutically acceptable carrier or excipient.

[0860] When administered in combination, either as a single or asseparate pharmaceutical composition(s), the CNS-penetrant NK-1 receptorantagonist and an antidepressant or anti-anxiety agent, are presented ina ratio which is consistent with the manifestation of the desiredeffect. In particular, the ratio by weight of the CNS-penetrant NK-1receptor antagonist and the antidepressant or anti-anxiety agent willsuitably be between 0.001 to 1 and 1000 to 1, and especially between0.01 to 1 and 100 to 1.

[0861] A suitable dosage level for the CNS-penetrant NK-1 receptorantagonist about 0.05 to 1500 mg per day, preferably about 0.25 to 1500mg per day, and especially about 0.25 to 500 mg per day. The compoundsmay be administered on a regimen of up to 6 times per day, preferably 1to 4 times per day, especially 2 times per day and most especially oncedaily.

[0862] A suitable dosage level for the antidepressant agent is about 0.5to 1500 mg per day, preferably about 2.5 to 1000 mg per day, andespecially about 2.5 to 500 mg per day. The compounds may beadministered on a regimen of up to 6 times per day, preferably 1 to 4times per day, especially 2 times per day and most especially oncedaily.

[0863] A suitable dosage level for the anti-anxiety agent is about 0.5to 1500 mg per day, preferably about 2.5 to 1000 mg per day, andespecially about 2.5 to 500 mg per day. The compounds may beadministered on a regimen of up to 6 times per day, preferably 1 to 4times per day, especially 2 times per day and most especially oncedaily.

[0864] It will be appreciated that the amount of the CNS-penetrant NK-1receptor antagonist and the antidepressant or anti-anxiety agentrequired for use in the treatment or prevention of depression and/oranxiety will vary not only with the particular compounds or compositionsselected but also with the route of administration, the nature of thecondition being treated, and the age and condition of the patient, andwill ultimately be at the discretion of the patient's physician orpharmacist.

[0865] As used herein the term “patient” includes animals of economicimportance such as bovine, ovine, and porcine animals, especially thosethat produce meat, as well as domestic animals (e.g. cats and dogs),sports animals (e.g. horses), zoo animals, and humans, the latter beingpreferred.

[0866] The compounds of formulae (I), (II), (III), (Iv) and (V) may beprepared by the methods described in EP-A-0 577 394 (or WO 95/16679), WO95/18124, WO 95/23798, WO 96/05181 and WO 96/07649, respectively.

[0867] As used herein, the term “CNS-penetrant” refers to NK-1 receptorantagonists which are able to inhibit NK-1 receptor antagonist-inducedfoot-tapping in the gerbil as hereinafter defined.

[0868] Essentially, hind foot-tapping in the gerbil induced by infusionof the NK-1 receptor agonist, GR73632 (dAla[_(L)-Pro⁹,Me-Leu¹⁰]-substance P (7-11)), under anaesthesia, directlyinto the central ventricles is inhibited when a CNS-penetrant NK-1receptor antagonist is administered intravenously immediately prior toGR73632 challenge, wherein hind foot-tapping over a period of fiveminutes following recovery from the anaesthesia is inhibited with anID₅₀≦3 mg/kg, and preferably with an ID₅₀≦1 mg/kg.

[0869] In an alternative method, the NK-1 receptor antagonist isadministered orally, 1 hour prior to GR73632 challenge, wherein thefoot-tapping over a period of five minutes following recovery fromanaesthesia is inhibited with an ID₅₀≦30 mg/kg, and preferably with anID₅₀≦10 mg/kg.

[0870] CNS-penetrant NK-1 receptor antagonists of use in the presentivnention are also effective in the attenuation of separation-inducedvocalisations by guinea-pig pups as hereinafter defined Essentially, avocalisation response in guinea-pig pups is induced by isolation fromtheir mothers and littermates, which response is attenuated when aCNS-penetrant NK-1 receptor antagonist is administered subcutaneously 30minutes prior to isolation, wherein vocalisations during the first 15minutes of isolation are attenuated with an ID₅₀≦20 mg/kg, preferablywith an ID₅₀≦10 mg/kg, and especially with an ID₅₀≦5 mg/kg.

[0871] In an alternative method, the NK-1 receptor antagonist isadministered orally, 4 hours prior to isolation, wherein vocalisationsduring the first 15 minutes of isolation are attenuated with an ID₅₀≦20mg/kg, preferably with an ID₅₀≦10 mg/kg, and especially with an ID₅₀≦5mg/kg.

[0872] Whilst it is recognised in many of the aforementioned patentspecifications that NK-1 receptor antagonists may be used to treatdepression and/or anxiety, there remains a need for simple and reliablemethods for the identification of compounds with NK-1 receptorantagonist activity which would be effective in the treatment ofdepression and/or anxiety.

[0873] The present invention accordingly provides a preclinical screenfor antidepressant and/or anxiolytic activity of CNS-penetrant NK-1receptor antagonists, which comprises:

[0874] a) to a guinea-pig pup, administration of a NK-1 receptorantagonist or vehicle by intravenous, subcutaneous, intraperitoneal ororal routes;

[0875] b1) 30-60 minutes after intravenous, subcutaneous orintraperitoneal administration, socially isolating the treatedguinea-pig pups by removal from their mother and littermates; or

[0876] b2) up to 4 hours after oral administration, socially isolatingthe treated guinea-pig pups by removal from their mother andlittermates;

[0877] c) recording the number or duration of vocalisations (isolationcalls) during a specified period and comparing the effects on guinea-pigpups treated with NK-1 receptor antagonists against their own baselineor against guinea-pig pups that receive no test compound or vehicle.

[0878] Preferably the NK-1 receptor antagonist is administered bysubcutaneous injection or orally by gavage.

[0879] An advantage of the present invention is that the guinea-pig is amammal with human-like NK-1 receptor pharmacology.

[0880] The guinea-pig preclinical screen described herein has been shownto be sensitive not only to the anxiolytic and antidepressant effects ofNK-1 receptor antagonists, but also to the effects of establishedanxiolytic and antidepressant drugs. Thus, for example, buspirone,diazepam, fluoxetine, and imipramine were all active in this assay(ID₅₀=0.5 mg/kg s.c., 0.7 mg/kg s.c., 2.7 mg/kg i.p. and 5.4 mg/kg s.c.,respectively).

[0881] According to a futher aspect of the present invention, there isprovided a preclinical screen for antidepressant and/or anxiolyticactivity of CNS-penetrant NK-1 receptor antagonists, which comprises:

[0882] a) to a gerbil, administration of a NK-1 receptor antagonist orvehicle by intravenous, subcutaneous, intraperitoneal or oral routes;

[0883] b) administration by injection under anaesthetic of NK-1 receptoragonists or anxiogenic agents, administered centrally or systemically;or subjecting the gerbil to stressors such as single housing or footshock;

[0884] c) recording the duration of repetitive hindfoot tapping andcomparing the effects on gerbils treated with NK-1 receptor antagonistsagainst gerbils that receive no test compound or vehicle.

[0885] Preferably the NK-1 receptor antagonist is administered byintravenous injection or orally by gavage.

[0886] Suitable NK-1 receptor agonists which elicit repetitive hindfoottapping include GR73632 (d-Ala[L-Pro⁹, Me-Leu¹⁰]substance P-(7-11)),[Sar⁹, Met(O₂)¹¹]substance P and substance P. Suitable anxiogenic agentsinclude pentagastrin and adrenaline.

[0887] The NK-1 receptor antagonist may be administered intravenouslyabout 5 minutes before challenge with the NK-1 receptor agonist oranxiogenic agent or before the aversive stimulation, in order to measurethe acute effect of the NK-1 receptor antagonist. If oral administrationis chosen, it may be preferable to administer the NK-1 receptorantagonist at least one hour prior to central injection of the NK-1receptor agonist or anxiogenic agent, or the aversive stimulus. In orderto measure the central duration of action of a NK-1 receptor antagonist,the test compound is conveniently administered approximately 24 hoursprior to central injection of the NK-1 receptor agonist or anxiogenicagent, or the aversive stimulus.

[0888] Whilst there are many different genera of gerbil, the preferredgenus is the Mongolian gerbil (Meriones unguiculatus). An advantage ofthe present invention is that the gerbil is a mammal with human-likeNK-1 receptor pharmacology.

[0889] The preclinical screens described herein have been shown to besensitive not only to the anxiolytic and antidepressant effects of NK-1receptor antagonists, but also to the effects of an establishedantidepressant drug, imipramine (ID₅₀=3.8 mg/kg s.c. followingfoot-tapping induced by substance P) and the anxiolytic drug, buspirone(ID₅₀=3.4 mg/kg s.c.).

[0890] The identification of CNS-penetrant NK₁ receptor antagonists ofuse as anxiolytic or antidepressant agents is carried out as follows:

[0891] (i) Determine affinity for human NK₁ receptor in radioligandbinding studies (Assay 1); select compounds with IC₅₀≦10 nM, preferablyIC₅₀≦2 nM, especially IC₅₀≦1 nM.

[0892] (ii) Determine activity of compounds for their ability to inhibitdistress vocalisations in guinea-pig pups (Assay 2)). Select compoundswith ID₅₀≦20 mg/kg, and preferably ID₅₀≦10 mg/kg, and especially ID₅₀≦5mg/kg.

[0893] According to an alternative aspect of the present invention, theidentification of NK₁ receptor antagonists of use as anxiolytic orantidepressant agents is carried out as follows:

[0894] (i) Determine affinity for human NK₁ receptor in radioligandbinding studies (Assay 1); select compounds with IC₅₀≦10 nM, preferablyIC₅₀≦2 nM, especially IC₅₀≦1 nM.

[0895] (ii) Determine ability of compounds to penetrate CNS by theirability to inhibit foot tapping in gerbils induced by central injectionof an NK₁ agonist (Assay 3); select compounds that inhibit foot tappingwith ID₅₀≦3 mg/kg i.v., and preferably ID₅₀≦1 mg/kg i.v. whenadministered immediately prior to central NK₁ agonist challenge, orID₅₀≦30 mg/kg p.o., and preferably ID₅₀≦10 mg/kg p.o. 1 hour prior tochallenge.

[0896] (iii) Determine central duration of action of compounds in gerbilfoot tapping assay following intravenous administration 24 hours priorto central NK₁ agonist challenge; select compounds showing ≦25-fold lossof potency compared with ID₅₀ determined in step (ii) above with theproviso that ID₅₀≦10 mg/kg i.v., and preferably ≦5 mg/kg i.v. after 24hour pre-treatment.

[0897] Yet further preferred compounds of use as anxiolytic orantidepressant agents may be selected, according to either of the“selection cascades” described above, from those compounds which satisfythe NK-1 receptor binding criteria of step (i) which, in addition, have≦5-fold shift in affinity when incubated in the presence of human serumalbumin (HSA) to show non-specific protein binding.

[0898] It will be appreciated that, if desired, the above “selectioncascades” may be combined. Thus, a further method for the identificationof NK-1 receptor antagonists of use as anxiolytic or antidepressantagents involves the use of Assay 1, Assay 2 and Assay 3, incorporatingthe selection criteria defined herein.

[0899] Particularly active CNS-penetrant NK-1 receptor antagonistsinclude:

[0900]2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;

[0901]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;

[0902]2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine;

[0903]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;

[0904]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;

[0905]2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;

[0906]2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine;

[0907] 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine;

[0908] or a pharmaceutically acceptable salt thereof.

[0909] According to a further aspect of the present invention, there isprovided the use of a CNS-penetrant NK-1 receptor antagonist identifiedaccording to either of the preclinical screens defined herein for themanufacture of a medicament for the treatment or prevention ofdepression and/or anxiety as previously defined.

[0910] Similarly, there is also provided a method for the treatment orprevention of depression and/or anxiety as previously defined, whichmethod comprises administration to a patient in need of such treatmentan effective amount of a CNS-penetrant NK-1 receptor antagonistidentified according to either of the preclinical screens definedherein.

[0911] Particularly preferred CNS-penetrant NK-1 receptor antagonists ofthe formulae (I), (II), (III), (IV) and (V) for use in the presentinvention are compounds which are potent NK-1 receptor antagonists, i.e.compounds with an NK-1 receptor affinity (IC₅₀) of less than 100 nM.Preferably, the NK-1 receptor antagonist has IC₅₀≦10 nM, in particularIC₅₀≦2 nM, and most especially IC₅₀≦1 nM.

[0912] NK-1 receptor binding assays are well known in the art. Thefollowing assay is one such protocol based upon the displacement of¹²⁵I-Tyr⁸-substance P binding to cloned human NK-1 receptors in vitro:

[0913] ASSAY 1: NK-1 Receptor Binding Assay

[0914] NK-1 receptor binding assays are performed in intact Chinesehamster ovary (CHO) cells expressing the human NK-1 receptor using amodification of the assay conditions described by Cascieri et al, J.Pharmacol. Exp. Ther., 1992, 42, 458. Typically, the receptor isexpressed at a level of 3×10⁵ receptors per cell. Cells are grown inmonolayer culture, detached from the plate with enzyme-free dissociationsolution (Speciality Media Inc.), and washed prior to use in the assay.¹²⁵I-Tyr⁸-substance P (0.1 nM, 2000 Ci/mmol; New England Nuclear) isincubated in the presence or absence of test compounds (dissolved in 5μl dimethylsulphoxide, DMSO) with 5×10⁴ CHO cells. Ligand binding isperformed in 0.25 ml of 50 mM Tris-HCl, pH7.5, containing 5 mM MnCl₂,150 mM NaCl, 0.02% bovine serum albumin (Sigma), 50 μg/ml chymostatin(Peninsula), 0.1 nM phenylmethylsulphonyl fluoride, 2 μg/ml pepstatin, 2μg/ml leupeptin and 2.8 μg/ml furoyl saccharine. The incubation proceedsat room temperature until equilibrium is achieved (>40 minutes) and thereceptor-ligand complex is harvested by filtration over GF/C filterspre-soaked in 0.1% polyethylenimine using a Tomtek 96-well harvester.Non-specific binding is determined using excess substance P (1 μM) andrepresents <10% of total binding.

[0915] Pharmacological assays for the study of antidepressant oranti-anxiety activity are well known in the art. Many are based upon theability of antidepressants to support animal behaviour in stressfulsituations that ordinarily lead to diminished behavioural responsiveness(“learned helplessness”), such as repeated noxious shocks, forcedswimming, or separation from other animals. For example, the followingassay, which involves the inhibition of separation-induced vocalisationsin guinea-pig pups, may be used to evaluate the methods of the presentinvention in the treatment or prevention of depression and/or anxiety.

[0916] ASSAY 2: Separation-induced Vocalisation

[0917] Male and female guinea-pigs pups are housed in family groups withtheir mothers and littermates throughout the study. Experiments arecommenced after weaning when the pups are at least 2 weeks old. Beforeentering an experiment, the pups may be screened to ensure that avigorous vocalisation response is reproducibly elicited followingmaternal separation. The pups are placed individually in an observationcage (approximately 55 cm×39 cm×19 cm) in a room physically isolatedfrom the home cage for approximately 15 minutes and the duration and/ornumber of vocalisation during this baseline period is recorded. Thoseanimals which vocalise for longer than 5 minutes may be employed fordrug challenge studies (approximately 50% of available pups may fail toreach this criterion). On test days each pup receives an oral dose or ans.c. or i.p. injection of test compound or vehicle and is thenimmediately returned to the home cage with its mother and siblings,typically for at least 30 to 60 minutes (or for up to 4 hours followingan oral dose, dependent upon the oral pharmacokinetics of the testcompound) before social isolation for 15 minutes as described above. Theduration and/or number of vocalisation on drug treatment days may beexpressed as a percentage of the pre-treatment baseline value for eachanimal or compared with values obtained in vehicle-treated animals. Thesame subjects may be retested once weekly for up to 6 weeks. Between 6and 8 animals typically receive each test compound at each dose tested.

[0918] ASSAY 3: Gerbil Foot-tapping (CNS Penetration) Assay

[0919] CNS-penetrant NK-1 receptor antagonists for use in the presentinvention can be identified by their ability to inhibit foot tapping ingerbils induced by anxiogenic agents (such as pentagastrin) or centralinfusion of NK-1 receptor agonists such as GR73632, or caused byaversive stimulation such as foot shock or single housing, based on themethod of Rupniak & Williams, Eur. J. Pharmacol., 1994, 265, 179.

[0920] Male or female Mongolian gerbils (35-70 g) are anaesthetised byinhalation of an isoflurane/oxygen mixture to permit exposure of thejugular vein in order to permit administration of test compounds orvehicle in an injection volume of approximately 5 ml/kg i.v.Alternatively, test compounds may be administered orally or bysubcutaneous or intraperitoneal routes. A skin incision is then made inthe midline of the scalp to expose the skull. An anxiogenic agent (e.g.pentagastrin) or a selective NK-1 receptor agonist (e.g. GR73632 (dAla[_(L)-Pro⁹,Me-Leu¹⁰]-substance P-(7-11)) is infused directly into thecerebral ventricles (e.g. 3 pmol in 5 μl i.c.v., depending on testsubstance) by vertical insertion of a cuffed 27 gauge needle to a depthof 4.5 mm below bregma. The scalp incision is closed and the animalallowed to recover from anaesthesia in a clear perspex observation box(approximately 25 cm×20 cm×20 cm). The duration and/or intensity of hindfoot tapping is then recorded continuously for approximately 5 minutes.Alternatively, the ability of test compounds to inhibit foot tappingevoked by aversive stimulation, such as foot shock or single housing,may be studied using a similar method of quantification.

[0921] It will be appreciated that CNS-penetration as defined by thisassay and as used herein is a property of the NK-1 receptor antagonistand is not conferred by co-administration or co-formulation of the NK-1receptor antagonist with a carrier or excipient designed to transientlyopen the blood-brain barrier.

[0922] One example of a NK-1 receptor antagonist active in thepreclinical screens of the present invention is the compound2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,the preparation of which is described in International PatentSpecification No. WO 95/16679. In the aforementioned assays, thiscompound has the following activity: human NK-1 receptor binding: IC₅₀ =0.1 nM guinea-pig vocalisation ID₅₀ = 0.73 mg/kg p.o. (4 hrs.pretreatment) gerbil foot-tapping (5 mins.): ID₅₀ = 0.36 mg/kg i.v.gerbil foot-tapping (24 hrs.): ID₅₀ = 0.33 mg/kg i.v.

[0923] Another example of a NK-1 receptor antagonist active in thepreclinical screens of the present invention is the compound2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine,the preparation of which is described in International PatentSpecification No. WO 95/18124. In the aforementioned assays, thiscompound has the following activity: human NK-1 receptor binding: IC₅₀ =0.25 nM guinea-pig vocalisation: ID₅₀ = 0.5 mg/kg s.c. gerbilfoot-tapping (5 mins.): ID₅₀ = 0.12 mg/kg i.v. gerbil foot-tapping (24hrs.): ID₅₀ = 0.17 mg/kg i.v.

[0924] Combinations of a CNS-penetrant NK-1 receptor antagonist with theanti-anxiety and antidepressant agents, buspirone and fluoxetine, havebeen tested in the guinea-pig vocalisation assay (Assay 3):

[0925] Test Compound A is2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine.

[0926] Test Compound B is the less active enantiomer of Test CompoundA—i.e.2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino)methyl-1,2,3-triazol-4-yl)methyl-3-(R)-phenylmorpholine.

[0927] Test Compounds A and B and buspirone were dissolved in 0.9%saline and administered s.c. in the flank. Due to limitations ofsolubility, fluoxetine was suspended in 0.5% methocel and given i.p. Theinjection volume was 1 ml/kg.

[0928] Results

[0929] Guinea-pig pups isolated from their mothers and littermatesemitted a vigorous vocalisation response during the first 15 minutes ofseparation (total duration approximately 8 minutes during this period).Administration of the highly CNS penetrant NK-1 receptor antagonist TestCompound A (0.25 mg/kg s.c.), buspirone (0.25 mg/kg s.c.), or fluoxetine(2 mg/kg i.p.) alone 30 minutes previously attenuated separation-inducedvocalisations by approximately 25% compared with the baselinevocalisation response determined using the same animals on the previousday. Combined administration of Test Compound A (0.25 mg/kg s.c.) witheither buspirone (0.25 mg/kg s.c.) or fluoxetine (2 mg/kg i.p.)virtually abolished separation-induced vocalisations (FIGS. 1 & 2). TheNK-1 receptor specificity of this effect was confirmed by the failure ofthe less active enantiomer, Test Compound B (0.25 mg/kg s.c.) toattenuate separation-induced vocalisations when administered alone, orto potentiate the inhibitory effect of buspirone (0.25 mg/kg s.c.; FIG.1).

[0930] The above results provide evidence for a synergistic interactionbetween a centrally acting NK-1 receptor antagonist (Test Compound A)with the anti-anxiety and antidepressant drugs buspirone and fluoxetinein a distress vocalisation assay using guinea-pigs. This appears toreflect a specific NK-1 receptor mediated interaction, sinceco-administration of the less active enantiomer, Test Compound B, at thesame dose failed to potentiate the ability of buspirone to inhibitvocalisations. The findings provide the first experimental evidence thatcentrally acting NK-1 receptor antagonists may augment the therapeuticresponse to clinically used anti-anxiety and antidepressant drugs,including agents acting as agonists or antagonists at the 5-HT_(1A)receptor (such as buspirone), and selective serotonin reuptakeinhibitors (such as fluoxetine).

[0931] It will be appreciated from the foregoing description that anadvantage of the combinations of the present invention is the oralbioavailability of the NK-1 receptor antagonists of use in suchcombinations. Pharmacokinetic analysis to determine the oralbioavailability of the NK-1 receptor antagonists may be effected simplyby measuring the ability of the NK-1 receptor antagonist to inhibit NK-1receptor agonist-induced foot-tapping in the gerbil following oraladministration of the NK-1 receptor antagonist. Compounds with anID₅₀≦30 mg/kg p.o., and preferably ID₅₀≦10 mg/kg p.o., followingadministration 1 hour prior to central NK-1 receptor agonist challengeare considered to be orally active according to the present invention.

[0932] An alternative pharmacokinetic analysis takes advantage of theability of CNS-penetrant NK-1 receptor antagonists to atenuatecisplatin-induced emesis. Orally active, CNS-penetrant NK-1 receptorantagonists demonstrate this activity in the following assay:

[0933] ASSAY 4: Ferret Emesis

[0934] Individually housed male ferrets (1.0-2.5 kg) are dosed orally bygavage with test compound. Ten minutes later they are fed withapproximately 100 g of tinned cat food. At 60 minutes following oraldosing, cisplatin (10 mg/kg) is given i.v. vic a jugular vein catheterinserted under a brief period of halothane anaesthesia. The catheter isthen removed, the jugular vein ligated and the skin incision closed. Theferrets recover rapidly from the anaesthetic and are mobile within 10-20minutes. The animals are observed continuously during recovery from theanaesthetic and for 4 hours following the cisplatin injection. Thenumbers of retches and vomits occurring during the 4 hours aftercisplatin administration are recorded by trained observers.

[0935] Oral bioavailability of the NK-1 receptor antagonist isdetermined by its ability to inhibit cisplatin-induced emesis in ferretsfollowing oral administration (Assay 4). Compounds with an ID₉₀≦3 mg/kgp.o., and preferably ID₉₀≦1 mg/kg p.o., are considered to be orallyactive according to the present invention. Thus, for example, the NK-1receptor antagonist2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,mentioned above, has an ID₉₀ in the ferret emesis assay (Assay 4) of <3mg/kg p.o.

[0936] The following examples illustrate pharmaceutical compositionsaccording to the invention.

[0937] These formulations may be prepared with separate activeingredients or with a combination of active ingredients in onecomposition. In such combined preparations, the ratio of theCNS-penetrant NK-1 receptor antagonist and the antidepressant oranti-anxiety agent will depend upon the choice of active ingredients.EXAMPLE 1 Tablets containing 50-300 mg of NK-1 antagonist and 5-10 mg ofbuspirone Amount mg NK-1 antagonist 50.0 50.0 100.0 100.0 300.0 300.0buspirone 5.0 10.0 5.0 10.0 5.0 10.0 Microcrystalline cellulose 80.080.0 80.0 80.0 80.0 80.0 Modified food corn starch 80.0 80.0 80.0 80.080.0 80.0 Lactose 184.5 179.5 134.5 129.5 134.5 129.5 Magnesium Stearate0.5 0.5 0.5 0.5 0.5 0.5

[0938] EXAMPLE 2 Tablets containing 50-300 mg of NK-1 antagonist and 20mg of fluoxetine Amount mg NK-1 antagonist 50.0 100.0 300.0 fluoxetine20.0 20.0 20.0 Microcrystalline cellulose 80.0 80.0 80.0 Modified foodcorn starch 80.0 80.0 80.0 Lactose 169.5 119.5 119.5 Magnesium Stearate0.5 0.5 0.5

[0939] The active ingredients cellulose, lactose and a portion of thecorn starch are mixed and granulated with 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulation isthen compressed into tablets containing 50 mg, 100 mg and 300 mg of theCNS-penetrant NK-1 receptor antagonist per tablet.

1. Use of a NK-1 receptor antagonist and an antidepressant oranti-anxiety agent for the manufacture of a medicament for the treatmentor prevention of depression and/or anxiety, characterised in that saidNK-1 receptor antagonist is CNS-penetrant as determined by its abilityto inhibit NK-1 receptor agonist-induced foot-tapping in the gerbil, andis effective in the attenuation of separation-induced vocalisations byguinea-pig pups, and wherein said medicament is adapted for oraladminsitration.
 2. Use as claimed in claim 1 wherein the NK-1 receptorantagonist inhibits NK-1 receptor agonist-induced foot-tapping in thegerbil with an ID₅₀≦3 mg/kg i.v. when administered immediately prior tocentral NK-1 receptor agonist challenge; or an ID₅₀≦30 mg/kg p.o. whenadministered 1 hour prior to central NK-1 receptor agonist challenge. 3.Use as claimed in claim 2 wherein the NK-1 receptor antagonistadditionally shows ≦25-fold loss of potency in its inhibition of NK-1receptor agonist-induced foot-tapping in the gerbil followingintravenous administration 24 hours prior to central NK-1 receptoragonist challenge, with the proviso that the ID₅₀≦10 mg/kg i.v. after 24hour pre-treatment.
 4. Use as claimed in any one of claims 1 to 3wherein the NK-1 receptor antagonist attenuates separation-inducedvocalisations by guinea-pig pups with an ID₅₀≦20 mg/kg.
 5. Use asclaimed in any one of claims 1 to 4 wherein the NK-1 receptor antagonisthas an affinity for the human NK-1 receptor of IC₅₀≦10 nM.
 6. Use asclaimed in any one of claims 1 to 5 wherein the NK-1 receptor antagonistis a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom the group consisting of: (1) C₁₋₆alkyl, substituted with one ormore of the substituents selected from: (a) heterocycle, wherein theheterocycle is selected from the group consisting of: (A)benzimidazolyl, (B) imidazolyl, (C) isoxazolyl, (D) isothiazolyl, (E)oxadiazolyl, (F) pyrazinyl, (G) pyrazolyl, (H) pyridyl, (I) pyrrolyl,(J) tetrazolyl, (K) thiadiazolyl, (L) triazolyl, and (M) piperidinyl,and wherein the heterocycle is unsubstituted or substituted with one ormore substituent(s) selected from: (i) C₁₋₆alkyl, unsubstituted orsubstituted with halo, —CF₃, —OCH₃, or phenyl, (ii) C₁₋₆alkoxy, (iii)oxo, (iv) thioxo, (v) cyano, (vi) —SCH₃, (vii) phenyl, (viii) hydroxy,(ix) trifluoromethyl, (x) —(CH²)_(m)—NR⁹R¹⁰, wherein m is 0, 1 or 2, andR⁹ and R¹⁰ are independently selected from: (I) hydrogen, (II)C₁₋₆alkyl, (III) hydroxyC₁₋₆alkyl, and (IV) phenyl, (xi) —NR⁹COR¹⁰,wherein R⁹ and R¹⁰ are as defined above, and (xii) —CONR⁹R¹⁰, wherein R⁹and R¹⁰ are as defined above, R² and R³ are independently selected fromthe group consisting of: (1) hydrogen; (2) C₁₋₆alkyl (3) C₂₋₆alkenyl,and (5) phenyl; X is —O—; R⁴ is

R⁵ is phenyl, unsubstituted or substituted with halo; R⁶, R⁷ and R⁸ areindependently selected from the group consisting of: (1) hydrogen, (2)C₁₋₆alkyl, (3) halo, and (4) —CF₃; Y is —O—; and Z is hydrogen orC₁₋₄alkyl.
 7. Use as claimed in any one of claims 1 to 5 wherein theNK-1 receptor antagonist is a compound of formula (IIa):

or a pharmaceutically acceptable salt thereof, wherein: A¹ is fluorineor CF₃; A² is fluorine or CF₃; A³ is fluorine or hydrogen; R⁶ is a5-membered or 6-membered heterocyclic ring containing 2 or 3 nitrogenatoms optionally substituted by ═O, ═S or a C₁₋₄alkyl group, andoptionally substituted by a group of the formula ZNR⁷R⁸ where Z isC₁₋₆alkylene or C₃₋₆cycloalkylene; R⁷ is hydrogen, C₁₋₄alkyl,C₃₋₇cycloalkyl or C₃₋₇cycloalkylC₁₋₄alkyl, or C₂₋₄alkyl substituted byC₁₋₄alkoxy or hydroxyl; R⁸ is hydrogen, C₁₋₄alkyl, C₃₋₇cycloalkyl orC₃₋₇cycloalkylC₁₋₄alkyl, or C₂₋₄alkyl substituted by one or twosubstituents selected from C₁₋₄alkoxy, hydroxyl or a 4, 5 or 6 memberedheteroaliphatic ring containing one or two heteroatoms selected from N,O and S; or R⁷, R⁸ and the nitrogen atom to which they are attached forma heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by ahydroxy group, and optionally containing a double bond, which ring mayoptionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)₂or a second nitrogen atom which will be part of a NH or NR^(c) moietywhere R^(c) is C₁₋₄alkyl optionally substituted by hydroxy orC₁₋₄alkoxy; or R⁷, R⁸ and the nitrogen atom to which they are attachedform a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Z,R⁷ and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms which may optionally containan oxygen ring atom; X is an alkylene chain of 1 to 4 carbon atomsoptionally substituted by oxo; and Y is a C₁₋₄alkyl group optionallysubstituted by a hydroxyl group; with the proviso that if Y isC₁₋₄alkyl, R⁶ is susbstituted at least by a group of formula ZNR⁷R⁸ asdefined above.
 8. Use as claimed in any one of claims 1 to 5 wherein theNK-1 receptor antagonist is a compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein: R² and R³ areindependently selected from the group consisting of: (1) hydrogen, (2)C₁₋₆alkyl, (3) C₂₋₆alkenyl, and (4) phenyl; R⁶, R⁷ and R⁸ areindependently selected from the group consisting of: (1) hydrogen, (2)C₁₋₆alkyl, (3) fluoro, (4) chloro, (5) bromo, (6) iodo, and (7) —CF₃;R¹¹, R¹² and R¹³ are independently selected from the group consistingof: (1) fluoro, (2) chloro, (3) bromo, and (4) iodo; A is unsubstituted₁₋₆alkyl; B is selected from the group consisting of:

p is 0 or 1; X is selected from: (a) —PO(OH)O⁻.M⁺, wherein M⁺ is apharmaceutically acceptable monovalent counterion, (b) —PO(O⁻)₂.2M⁺, (c)—PO(O⁻)₂.D²⁺, wherein D²⁺ is a pharmaceutically acceptable divalentcounterion, (d) —CH(R⁴)—PO(OH)O⁻.M⁺, wherein R⁴ is hydrogen orC₁₋₃alkyl, (e) —CH(R⁴)—PO(O⁻)₂.2M⁺, (f) —CH(R⁴)—PO(O⁻)₂.D²⁺, (i)—CO—CH₂CH₂—CO₂ ⁻.M⁺, (j) —CH(CH₃)—O—CO—R⁵, wherein R⁵ is selected fromthe group consisting of:

Y is —O—; and Z is hydrogen or C₁₋₆alkyl.
 9. Use as claimed in any oneof claims 1 to 5 wherein the NK-1 receptor antagonist is a compound offormula (IVa):

or a pharmaceutically acceptable salt thereof, wherein: A¹ is fluorineor CF₃; A² is fluorine or CF₃; A³ is fluorine or hydrogen; X is a groupof the formula NR⁶R⁷ or a C- or N-linked imidazolyl ring; Y is hydrogenor C₁₋₄alkyl optionally substituted by a hydroxy group; R⁶ is hydrogen,C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, phenyl, or C₂₋₄alkylsubstituted by C₁₋₄alkoxy or hydroxy; R⁷ is hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, phenyl, or C₂₋₄alkylsubstituted by one or two substituents selected from C₁₋₄alkoxy, hydroxyor a 4, 5 or 6 membered heteroaliphatic ring containing one or twoheteroatoms selected from N, O and S; or R⁶ and R⁷, together with thenitrogen atom to which they are attached, form a saturated or partiallysaturated heterocyclic ring of 4 to 7 ring atoms, which ring mayoptionally contain in the ring one oxygen or sulphur atom or a groupselected from NR⁸, S(O) or S(O)₂ and which ring may be optionallysubstituted by one or two groups selected from hydroxyC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, oxo, COR^(a) or CO₂R^(a) where R^(a) is hydrogen orC₁₋₄alkyl; or R⁶ and R⁷ together with the nitrogen atom to which theyare attached, form a non-aromatic azabicyclic ring system of 6 to 12ring atoms; and R⁸ is hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl orC₁₋₄alkoxyC₁₋₄alkyl.
 10. Use as claimed in any one of claims 1 to 5wherein the NK-1 receptor antagonist is a compound of formula (Va):

or a pharmaceutically acceptable salt thereof, wherein: A¹ is hydrogen,fluorine or CF₃; A² is fluorine or CF₃; A³ is fluorine or hydrogen; R⁶is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, phenyl,or C₂₋₄alkyl substituted by C₁₋₄alkoxy or hydroxy; R⁷ is hydrogen,C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, phenyl, C₂₋₄alkylsubstituted by C₁₋₄alkoxy or hydroxy, or the groupC(═NR^(c))NR^(a)R^(b), where R^(a) and R^(b) are each independentlyhydrogen or C₁₋₄alkyl and R^(c) is hydrogen, C₁₋₆alkyl, CN or COR^(a);or R⁶ and R⁷, together with the nitrogen atom to which they areattached, form a saturated heterocyclic ring of 4 to 7 ring atoms whichmay optionally contain in the ring one oxygen or sulphur atom or a groupselected from NR⁸, S(O) or S(O)₂ and which ring may be optionallysubstituted by one or two groups selected from phenyl, benzyl,hydroxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, hydroxy, oxo, COR^(a) or CO₂R^(a)where R^(a) is as previously defined; or R⁶ and R⁷, together with thenitrogen atom to which they are attached, form a piperidino ringsubstituted by a spiro-fused indene or indoline group, each of which maybe unsubstituted or substituted on any available carbon atom by a groupselected from C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, halogen, cyano,trifluoromethyl, SO₂C₁₋₆alkyl, NR^(a)R^(b), NR^(a)COR^(b) orCONR^(a)R^(b); or, in the case of an indoline group, on the nitrogenatom by a group selected from C₁₋₆alkyl, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, phenylC₁₋₄alkyl, CO₂R^(a), CONR^(a)R^(b),SOR^(a) or SO₂R^(a), where R^(a) and R^(b) are as previously defined; R⁸is hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl; X isselected from —CH₂CH₂—, —COCH₂— or —CH₂CO—; and Y is hydrogen, orC₁₋₄alkyl optionally substituted by a hydroxyl group.
 11. Use as claimedin any one or claims 1 to 10 wherein the antidepressant agent isselected from norepinephrine reuptake inhibitors, selective serotoninreuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs),reversible inhibitors of monoamine oxidase (RIMAs), serotonin andnoradrenaline reuptake inhibitors (SNRIs), corticotropin releasingfactor (CRF) antagonists, α-adrenoreceptor antagonists, atypicalantidepressants, and noradrenergic and specific serotonergicantidepressants (NaSSAs).
 12. Use as claimed in any one of claims 1 to10 wherein the anti-anxiety agent is selected from benzodiazepines,5-HT_(1A) agonists, antagonists or partial agonists, corticotropinreleasing factor (CRF) antagonists and m1 muscarinic cholinergicreceptor agonists.
 13. An oral pharmaceutical composition comprising aNK-1 receptor antagonist and an antidepressant or anti-anxiety agent,together with at least one pharmaceutically acceptable carrier orexcipient, characterised in that said NK-1 receptor antagonist isCNS-penetrant as determined by its ability to inhibit NK-1 receptoragonist-induced foot-tapping in the gerbil, and is effective in theattenuation of separation-induced vocalisations by guinea-pig pups. 14.A product comprising a NK-1 receptor antagonist and an antidepressant oranti-anxiety agent as a combined preparation for simultaneous, separateor sequential use in the treatment or prevention of depression and/oranxiety, characterised in that said NK-1 receptor antagonist isCNS-penetrant as determined by its ability to inhibit NK-1 receptoragonist-induced foot-tapping in the gerbil, and is effective in theattenuation of separation-induced vocalisations by guinea-pig pups. 15.A method for the treatment or prevention of depression and/or anxiety,which method comprises oral administration to a patient in need of suchtreatment an amount of a NK-1 receptor antagonist and an amount of anantidepressant or anti-anxiety agent, such that together they giveeffective relief, wherein said NK-1 receptor antagonist is CNS-penetrantas determined by its ability to inhibit NK-1 receptor agonist-inducedfoot-tapping in the gerbil, and is effective in the attenuation ofseparation-induced vocalisations by guinea-pig pups.
 16. A method asclaimed in claim 15 wherein the NK-1 receptor antagonist is selectedfrom the compounds of any one of formulae (I), (IIa), (III), (IVa) and(Va) as defined in claims 6 to
 10. 17. A method as claimed in claim 15wherein the antidepressant agent is selected from the group consistingof: norepinephrine reuptake inhibitors, selective serotonin reuptakeinhibitors, monoamine oxidase inhibitors, reversible monoamine oxidaseinhibitors, serotonin and noradrenaline reuptake inhibitors,corticotropin releasing factor (CRF) antagonists, α-adrenoreceptorantagonists and atypical antidepressants.
 18. A method as claimed inclaim 15 wherein the anti-anxiety agent is selected from the groupconsisting of benzodiazepines, 5-HT_(1A) agonists, antagonists orpartial agonists, corticotropin releasing factor antagonists and m1muscarinic cholinergic receptor agonists.
 19. A method for theidentification of antidepressant and/or anxiolytic activity ofCNS-penetrant NK-1 receptor antagonists, which comprises: a) to aguinea-pig pup, administration of a NK-1 receptor antagonist or vehicleby intravenous, subcutaneous, intraperitoneal or oral routes; b1) 30-60minutes after intravenous, subcutaneous or intraperitonealadministration, socially isolating the treated guinea-pig pups byremoval from their mother and littermates; or b2) up to 4 hours afteroral administration, socially isolating the treated guinea-pig pups byremoval from their mother and littermates; and c) recording the numberor duration of vocalisations (isolation calls) during a specified periodand comparing the effects on guinea-pig pups treated with NK-1 receptorantagonists against their own baseline or against guinea-pig pups thatreceive no test compound or vehicle.
 20. A method for the identificationof antidepressant and/or anxiolytic activity of CNS-penetrant NK-1receptor antagonists, which comprises: a) to a gerbil, administration ofa NK-1 receptor antagonist or vehicle by intravenous, subcutaneous,intraperitoneal or oral routes; b) administration by injection underanaesthetic of NK-1 receptor agonists or anxiogenic agents, administeredcentrally or systemically; or subjecting the gerbil to stressors such assingle housing or foot shock; and c) recording the duration ofrepetitive hindfoot tapping and comparing the effects on gerbils treatedwith NK-1 receptor antagonists against gerbils that receive no testcompound or vehicle.
 21. A method as claimed in claim 19 or claim 20wherein the NK-1 receptor antagonist is administered by intravenousinjection or orally by gavage.
 22. A method for the identification ofCNS-penetrant NK-1 receptor antagonists of use as anxiolytic orantidepressant agents which comprises: (i) Determine affinity for humanNK-1 receptor in radioligand binding studies and select compounds withIC₅₀≦10 nM; and (ii) Determine activity of compounds for their abilityto inhibit distress vocalisations in guinea-pig pups and selectcompounds with ID₅₀≦20 mg/kg.
 23. A method for the identification ofNK-1 receptor antagonists of use as anxiolytic or antidepressant agentswhich comprises: (i) Determine affinity for human NK-1 receptor inradioligand binding studies and select compounds with IC₅₀≦10 nM; (ii)Determine ability of compounds to penetrate CNS by their ability toinhibit foot tapping in gerbils induced by central injection of an NK-1agonist and; select compounds that inhibit foot tapping with ID₅₀≦3mg/kg i.v., when administered immediately prior to central NK-1 agonistchallenge, or ID₅₀≦30 mg/kg p.o. when administered 1 hour prior tocentral NK-1 agonist challenge; and (iii) Determine central duration ofaction of compounds in gerbil foot tapping assay following intravenousadministration 24 hours prior to central NK-1 agonist challenge andselect compounds showing ≦25-fold loss of potency compared with ID₅₀determined in step (ii) above with the proviso that ID₅₀≦10 mg/kg i.v.after 24 hour pre-treatment.
 24. A method as claimed in claim 22 orclaim 23 which comprises the identification of compounds which satisfythe NK-1 receptor binding criteria of step (i) and which, in addition,have ≦5-fold shift in affinity when incubated in the presence of humanserum albumin (HSA).
 25. Use of a CNS-penetrant NK-1 receptor antagonistidentified according to a method as claimed in any one of claims 19 to24 for the manufacture of a medicament for the treatment or preventionof depression and/or anxiety.
 26. A method for the treatment orprevention of depression and/or anxiety, which method comprisesadministration to a patient in need of such treatment an effectiveamount of a CNS-penetrant NK-1 receptor antagonist identified accordingto the method of claim 20 or claim 21.